Imidazopyridazines as akt kinase inhibitors

ABSTRACT

Imidazopyridazines of formula (I) 
     
       
         
         
             
             
         
       
     
     a process for their production and the use thereof.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to substituted Imidazopyridazines, a process fortheir production and the use thereof.

KNOWN TECHNICAL BACKGROUND

Cancer is the second most prevalent cause of death in the United States,causing 450,000 deaths per year. While substantial progress has beenmade in identifying some of the likely environmental and hereditarycauses of cancer, there is a need for additional therapeutic modalitiesthat target cancer and related diseases. In particular there is a needfor therapeutic methods for treating diseases associated withdysregulated growth/proliferation.

Cancer is a complex disease arising after a selection process for cellswith acquired functional capabilities like enhanced survival/resistancetowards apoptosis and a limitless proliferative potential. Thus, it ispreferred to develop drugs for cancer therapy addressing distinctfeatures of established tumors.

One pathway that has been shown to mediate important survival signalsfor mammalian cells comprises receptor tyrosine kinases likeplatelet-derived growth factor receptor (PDGF-R), human epidermal growthfactor 2/3 receptor (HER2/3), or the insulin-like growth factor 1receptor (IGF-1R). After activation the respectives by ligand, thesereceptors activate the phoshatidylinositol 3-kinase (Pi3K)/Akt pathway.The phoshatidylinositol 3-kinase (Pi3K)/Akt protein kinase pathway iscentral to the control of cell growth, proliferation and survival,driving progression of tumors. Therefore within the class ofserine-threonine specific signalling kinases, Akt (protein kinase B;PKB) with the isoenzmyes Akt1 (PKBα), Akt2 (PKB β) and Akt3 (PKB γ) isof high interest for therapeutic intervention. Akt is mainly activatedin a Pi3-kinase dependent manner and the activation is regulated throughthe tumor suppressor PTEN (phosphatase and tensin homolog), which worksessentially as the functional antagonist of Pi3K.

The Pi3K/Akt pathway regulates fundamental cellular functions (e.g.transcription, translation, growth and survival), and is implicated inhuman diseases including diabetes and cancer. The pathway is frequentlyoveractivated in a wide range of tumor entities like breast and prostatecarcinomas. Upregulation can be due to overexpression or constitutivelyactivation of receptor tyrosine kinases (e.g. EGFR, HER2/3), which areupstream and involved in its direct activation, or gain- orloss-of-function mutants of some of the components like loss of PTEN.The pathway is targeted by genomic alterations including mutation,amplification and rearrangement more frequently than any other pathwayin human cancer, with the possible exception of the p53 andretinoblastoma pathways. The alterations of the Pi3K/Akt pathway triggera cascade of biological events, that drive tumor progression, survival,angiogenesis and metastasis.

Activation of Akt kinases promotes increased nutrient uptake, convertingcells to a glucose-dependent metabolism that redirects lipid precursorsand amino acids to anabolic processes that support cell growth andproliferation. These metabolic phenotype with overactivated Akt lead tomalignancies that display a metabolic conversion to aerobic glycolysis(the Warburg effect). In that respect the Pi3K/Akt pathway is discussedto be central for survival despite unfavourable growth conditions suchas glucose depletion or hypoxia.

A further aspect of the activated PI3K/Akt pathway is to protect cellsfrom programmed cell death (“apoptosis”) and is hence considered totransduce a survival signal. By acting as a modulator of anti-apoptoticsignalling in tumor cells, the Pi3K/Akt pathway, particularly Akt itselfis a target for cancer therapy. Activated Akt phosphorylates andregulates several targets, e.g. BAD, GSK3 or FKHRL1, that affectdifferent signalling pathways like cell survival, protein synthesis orcell movement. This Pi3K/Akt pathway also plays a major part inresistance of tumor cells to conventional anti-cancer therapies.Blocking the Pi3K/Akt pathway could therefore simultaneously inhibit theproliferation of tumor cells (e.g. via the inhibition of the metaboliceffect) and sensitize towards pro-apoptotic agents.

Akt inhibition selectively sensitized tumor cells to apoptotic stimulilike Trail, Campthothecin and Doxorubicin. Dependent on the geneticbackground/molecular apperations of tumors, Akt inhibitors might induceapoptotic cell death in monotherapy as well.

Thus Akt seems to be a suitable target for the treatment of cancer.

Various publications exist relating to Akt inhibiting compounds such ase.g. WO 2009/148887, WO 2009/148916, WO2010104933, WO2010114780,WO2011033265.

In a recent disclosure, Y. Li et al (Bioorg. Med. Chem. Lett. 2009, 19,834-836 and cited references therein) detail the difficulty in findingoptimal Akt inhibitors. The potential application of Akt inhibitors inmultiple disease settings, such as for example, cancer, makes theprovision of new Akt inhibitors to those currently available highlydesirable.

DESCRIPTION OF THE INVENTION

A solution to the above problem is the provision of alternative Aktinhibitors. It has now been found that the new Imidazopyridazinecompounds, which are described in detail below, are Akt inhibitorssuitable for the treatment of cancer.

In accordance with a first aspect, the invention relates to compounds offormula (I)

in whichR1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,—S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from 1-6C-alkyl,1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl,2-6C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7-cycloalkyl, 3-7C-heterocyclyl, aryl,R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,—S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from 1-6C-alkyl,1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl,2-6C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7C-heterocyclyl, aryl,R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-6C-alkyl,—S(O)₂NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl,NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7C-heterocyclyl, aryl,R4 is phenyl which is optionally substituted one, two or three times,identically or differently, with a halogen atom;R5 is hydrogen, 1-6C-alkyl,R6 is hydrogen, 1-6C-alkyl,R8 is hydrogen, 1-6C-alkyl which optionally is substituted with hydroxy,R9 is hydrogen, 1-6C-alkyl,R10 is hydrogen, 1-6C-alkyl,R11 is hydrogen, 1-6C-alkyl,

X, Y is CH₂;

n is 0, 1, 2;or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

In accordance with a second aspect, the invention relates to compoundsof formula (I) according to claim 1, wherein

-   R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from    1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,    -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl),    —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl,    —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl),    —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-7C-heterocyclyl, aryl,-   R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from    1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,    -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl),    —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl,    —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl),    —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-7C-heterocyclyl, aryl,-   R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from    1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,    -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl),    —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl,    —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl),    —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-7C-heterocyclyl, aryl,-   R4 is phenyl which is optionally substituted one, two or three    times, identically or differently, with a halogen atom;-   R5 is hydrogen, 1-6C-alkyl,-   R6 is hydrogen, 1-6C-alkyl,-   R8 is hydrogen, 1-6C-alkyl,-   R9 is hydrogen, 1-6C-alkyl,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is hydrogen, 1-6C-alkyl,-   X, Y is CH₂;-   n is 0, 1, 2;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention relates to compounds of formula (I)according to claim 1, wherein

-   R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-3C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-3C-alkyl, —S(O)₂NR5R6 or a group selected from    1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl,    -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl),    —O-aryl, —O-(3-6C-heterocyclyl), —O-heteroaryl,    —O-(1-3C-alkyl)-heteroaryl, —O-(1-3C-alkyl)-(3-6C-heterocyclyl),    —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-6-cycloalkyl, 3-6C-heterocyclyl, aryl,-   R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-3C-alkyl, —S(O)₂NR5R6 or a group selected from    1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl,    -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl),    —O-aryl, —O-(3-6C-heterocyclyl), —O-heteroaryl,    —O-(1-3C-alkyl)-heteroaryl, —O-(1-3C-alkyl)-(3-6C-heterocyclyl),    —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-6C-heterocyclyl, aryl,-   R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-3C-alkyl,    —S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy    3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,    -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,    —O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,    —O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl,    NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-6C-heterocyclyl, aryl,-   R4 is phenyl which is optionally substituted one, two or three    times, identically or differently, with a halogen atom;-   R5 is hydrogen, 1-3C-alkyl,-   R6 is hydrogen, 1-3C-alkyl,-   R8 is hydrogen, 1-3C-alkyl which optionally is substituted with    hydroxy,-   R9 is hydrogen, 1-3C-alkyl,-   R10 is hydrogen, 1-3C-alkyl,-   R11 is hydrogen, 1-3C-alkyl,-   X, Y is CH₂;-   n is 0, 1, 2;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention relates to compounds of formula (I)according to claim 1, wherein

-   R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8,    NHC(O)(1-6C-alkyl), or a group selected from 1-3C-alkyl,    1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl,        3-6C-heterocyclyl, aryl,-   R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11,    —S(O)_(n)-1-3C-alkyl, —S(O)₂NR5R6 or a group selected from    1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl,    -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl),    —O-aryl, —O-(3-6C-heterocyclyl), —O-heteroaryl,    —O-(1-3C-alkyl)-heteroaryl, —O-(1-3C-alkyl)-(3-6C-heterocyclyl),    —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-6C-heterocyclyl, aryl,-   R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,    C(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-3C-alkyl,    —S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy    3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,    -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,    —O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,    —O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl,    NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy,        —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11,        —NHS(O)₂R11, 3-6C-heterocyclyl, aryl,-   R4 is phenyl which is optionally substituted one, two or three    times, identically or differently, with a halogen atom;-   R5 is hydrogen, 1-3C-alkyl,-   R6 is hydrogen, 1-3C-alkyl,-   R8 is hydrogen, 1-3C-alkyl which optionally is substituted with    hydroxy,-   R9 is hydrogen, 1-3C-alkyl,-   R10 is hydrogen, 1-3C-alkyl,-   R11 is hydrogen, 1-3C-alkyl,-   X, Y is CH₂;-   n is 0, 1, 2;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention relates to compounds of formula (I)according to claim 1, wherein

-   R1 is OR7;-   R2 is hydrogen,-   R3 is C(O)NR8R9, C(O)OR8, halogen, 1-6C-alkyl, 1-6C-alkoxy,-   R4 is phenyl which is optionally substituted one, two or three    times,-   identically or differently, with a halogen atom;-   R5 is hydrogen, 1-6C-alkyl,-   R6 is hydrogen, 1-6C-alkyl,-   R7 is 1-4C-haloalkyl,-   R8 is hydrogen, 1-6C-alkyl,-   R9 is hydrogen, 1-6C-alkyl,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is hydrogen, 1-6C-alkyl,-   X, Y is CH₂;-   n is 0, 1, 2;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1,

wherein

-   R1 is hydrogen, 1-4C-alkoxy,-   R2 is hydrogen,-   R3 is C(O)NH₂, C(O)OR8, halogen, 1-4C-alkyl, 1-4C-alkoxy,-   R4 is phenyl which is optionally substituted one, two or three    times, identically or differently, with a halogen atom;-   R5 is hydrogen, 1-4C-alkyl,-   R6 is hydrogen, 1-4C-alkyl,-   R7 is 1-4C-haloalkyl,-   R8 is hydrogen, 1-4C-alkyl,-   R9 is hydrogen, 1-4C-alkyl,-   R10 is hydrogen, 1-4C-alkyl,-   R11 is hydrogen, 1-4C-alkyl,-   X, Y is CH₂-   n is 0, 1, 2;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein

-   R1 is hydrogen, methoxy, ethoxy,-   R2 is hydrogen,-   R3 is C(O)NH₂, C(O)OR8, 1-3C-alkyl, bromine, methoxy, ethoxy,-   R4 is phenyl which is optionally substituted one, two or three    times, identically or differently, with a halogen atom;-   R5 is hydrogen, 1-4C-alkyl,-   R6 is hydrogen, 1-4C-alkyl,-   R7 is 1-4C-haloalkyl,-   R8 is hydrogen, 1-4C-alkyl,-   R9 is hydrogen, 1-4C-alkyl,-   R10 is hydrogen, 1-4C-alkyl,-   R11 is hydrogen, 1-4C-alkyl,-   X, Y is CH₂    n is 0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of    said compound, or a salt of said N-oxide, tautomer or stereoisomer

A further aspect of the invention are compounds of formula (I)

wherein

-   R1 is hydrogen, 1-3C-alkoxy,-   R2 is hydrogen-   R3 is 1-3C-alkyl 1-3C-alkoxy, halogen, trifluoromethyl, C(O)NH2,    COOR8,-   R4 is phenyl-   R8 is hydrogen, 1-4C-alkyl,-   X, Y is CH2    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I)

whereinR1 is hydrogen, hydroxyl, amino, methoxy, ethoxy, butoxy, pyridine-3-yl,pyridine-4-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl, imidazole-2-yl,methyl, propyl, —O—(CH₂)—O—CH₃, —O—CH₂-phenyl, —O—CH₂-cyclopropyl,—C(O)OCH₃, —C(O)—NHCH₃, —C(O)—NH₂, 4-fluoro-phenyl, —(CH₂)₂—C(O)OCH₃,cyclopropyl, —NH—C(O)CH₃,R2 is hydrogen, methyl,R3 is hydrogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy,—O—CH₂—C(O)OCH₃, —S—CH₃, —SO₂—CH₃, bromine, chlorine, trifluoromethyl,C(O)NH₂, COOH, C(O)OCH₃, C(O)OCH₂CH₃, C(O)NH₂, C(O)NHCH₃, C(O)N(CH₃)₂,C(O)NH(CH₂)₂—OH, —CH═CH₂, 4-fluoro-phenyl, NHC(O)CH₃, NHC(O)CF₃,NH—SO₂—CH₃, C(O)CH₃,R4 is phenyl

X, Y is CH2

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I) wherein

-   R1 is hydrogen, methoxy,-   R2 is hydrogen-   R3 is methyl, ethyl, methoxy, bromine, trifluoromethyl, C(O)NH₂,    COOH, C(O)OCH₃, C(O)OCH₂CH₃,-   R4 is phenyl-   X, Y is CH2    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In one aspect of the invention compounds of formula (I) as describedabove are selected from the group consisting of:

1-[4-(6-Methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-[4-(6-Ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-{4-[3-Phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine Ethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide1-[4-(6-Methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6-carboxylic acid1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide1-[4-(8-Methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate1-[4-(6-Ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[6-Methoxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanami1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine HCl salt1-[4-(6,8-Diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(6-Chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-[4-(8-Methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[6-Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(3-Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]- cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[8-(Benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6-Chloro-8-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]- pyridazin-8-ol1-{4-[6-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6,8-dicarboxamide2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-amine1-{4-[6-(Methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}acetamideN-{2-[4-(1-1-{4-[6-(Methylsulfonyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylateN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}-2,2,2-trifluoroacetamide1-[4-(6-Bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine 1-{4-[6,8-Bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}ethanone1-{4-[8-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}methanesulfonamide1-[4-(6-Chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutanamine1-[4-(3-Phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-amineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-yl}acetamide1-[4-(6-Chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide1-[4-(6-Methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[7,8-Dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6-Ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate tert-Butyl{1-[4-(8-acetamido-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutyl}carbamate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-8-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-ethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide Methyl3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-imidazo[1,2-b]pyridazin-8-yl}propanoate1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Methoxy-8-(1-methyl-1H-pyrazol-5-yl)-3-phenyl-imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Methoxy-3-phenyl-8-(pyridin-4-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6,8-Diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(8-Butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-[4-(6-Ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]- pyridazin-6-olMethyl ({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo-[1,2-b]pyridazin-6-yl}oxy)acetate

One aspect of the present invention are the compounds disclosed in theexamples as well as the intermediates, especially a compound of generalformula (II) shown below in scheme 1, as used for their synthesis.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl),or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl,heteroaryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl,3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl),or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl,heteroaryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl),or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl,3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl),or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl,3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is hydrogen, —C(O)NH(1-3C-alkyl), —C(O)NH2 or a group selected from1-6C-alkoxy, heteroaryl which are optionally substituted with1-3C-alkyl, 1-3C-alkoxy.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R1 is 1-6C-alkoxy, preferably 1-4-alkyoxy, especially methoxy.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R2 is hydrogen.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-6C-alkyl,—S(O)₂NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl,NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-3C-alkyl,—S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,-(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,—O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,—O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl,NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R3 is hydrogen, hydroxy, amino, bromine, methoxy, ethoxy, butoxy,pyridine-3-yl, pyridine-4-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl,imidazole-2-yl, methyl, propyl, —O—(CH₂)—O—CH₃, —O—CH₂-phenyl,—O—CH₂-cyclopropyl, —C(O)OCH₃, —C(O)—NHCH₃, —C(O)—NH₂, 4-fluoro-phenyl,—(CH₂)₂—C(O)OCH₃, cyclopropyl, —NH—C(O)CH₃,

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

-   R3 is 1-4C-alkyl, COOR8, (CO)NH2, 1-4C-alkoxy, halogen, especially    methyl, ethyl, trifluoromethyl, aminocarbonyl, methoxy,    methoxycarbonyl, ethoxycarbonyl, COOH, bromine.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R3 is NR8R9, —C(O)OR10, —C(O)NR8R9.

In another embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I) according to claim 1, wherein R4 isan unsubstituted phenyl moiety.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

R8 is hydrogen, 1-4Calkyl, especially hydrogen or 1-2C-alkyl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein n is 0 or 2.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein R1 is selected from the following groups:

hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or agroup selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl,heteroaryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:halogen, 1-3C-alkyl, 1-3C-alkoxy, —C(O)OR10, 3-6-cycloalkyl,3-6C-heterocyclyl, arylandR3 is selected fromhydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)n-1-3C-alkyl,—S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,-(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,—O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,—O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl,NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from:hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-6C-heterocyclyl, aryl.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein R1 is selected from the following groups:

is hydrogen, —C(O)NH(1-3C-alkyl), —C(O)NH2 or a group selected from1-6C-alkoxy, heteroaryl which are optionally substituted with1-3C-alkyl, 1-3C-alkoxy and R3 is —C(O)NR8R9.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein R1 is selected from the following groups:

is hydrogen, —C(O)NH(1-3C-alkyl), —C(O)NH2 or a group selected from1-6C-alkoxy, heteroaryl which are optionally substituted with1-3C-alkyl, 1-3C-alkoxy and R3 is NR8R9.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein R1 is selected from the following groups:

is hydrogen, —C(O)NH(1-3C-alkyl), —C(O)NH2 or a group selected from1-6C-alkoxy, heteroaryl which are optionally substituted with1-3C-alkyl, 1-3C-alkoxy and R3 is —C(O)OR10.

Another aspect of the invention are compounds of formula (I) accordingto claim 1, wherein R1 is selected from the following groups:

is hydrogen, —C(O)NH(1-3C-alkyl), —C(O)NH2 or a group selected from1-6C-alkoxy, heteroaryl which are optionally substituted with1-3C-alkyl, 1-3C-alkoxy and R3 is 1-4C-alkyl, COOR8, (CO)NH2,1-4C-alkoxy, halogen, especially methyl, ethyl, trifluoromethyl,aminocarbonyl, methoxy, methoxycarbonyl, ethoxycarbonyl, COOH, bromine

DEFINITIONS

“1-6C-alkyl” is a straight-chain or branched alkyl group having 1 to 6carbon atoms. Examples are methyl, ethyl, n propyl, iso-propyl, n butyl,iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4carbon atoms (1-4C-alkyl), more preferably 1-3 carbon atoms(1-3C-alkyl). Other alkyl constituents mentioned herein having anothernumber of carbon atoms shall be defined as mentioned above taking intoaccount the different length of their chain. Whenever “alkyl” is part ofa constituent consisting of “alkyl” together with another component thedefinition of “alkyl” given above also applies.

The term “1-6C-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“2-3C-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “2-6C-alkynyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains one ormore triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“2-3C-alkynyl”). Said C2-C6-alkynylgroup is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group isethynyl, prop-1-ynyl, or prop-2-inyl.

NR5R6 represents “amino” as well as “mono- or di-1-6C-alkylamino”radicals containing in addition to the nitrogen atom, independently oneor two of the above mentioned 1-6C-alkyl radicals. Examples are themethyamino, the ethylamino, the isopropylamino, the dimethylamino, thediethylamino, the methyl(ethyl)amino and the diisopropylamino radicalThe same is intended for any NRxRy residue mentioned within the claimsor description.

“Aryl” represents a mono-, or bicyclic aromatic carbocyclic radicalhaving, as a rule, 6 to 10 carbon atoms; by way of example phenyl ornaphthyl. Phenyl is preferred.

The term “-(1-6C-alkyl)-aryl” represents an aryl radical as definedabove which is connected to the rest of the molecule via a straight orbranched alkyl chain, preferably —(CH₂)-aryl, or —(CH₂CH₂)-aryl. Benzylis particularly preferred.

The term “aryloxy” or “—O-aryl” represents the same aryl moieties asdefined for the term aryl whereby the ring is connected via an oxygenatom to the rest of the molecule.

The term “—O-(1-6C-alkyl)-aryl” represents the same aryl moieties asdefined for the term aryl whereby the ring is connected via a—O-(1-6Calkyl) spacer to the rest of the molecule. Preferred—O-(1-6Calkyl) spacers in this context are —O—(CH₂)—, or —O—(CH₂CH₂)—.Benzyloxy is particularly preferred.

“Halogen” within the meaning of the present invention is iodine,bromine, chlorine or fluorine, preferably “halogen” within the meaningof the present invention is chlorine or fluorine, if halogen were usedas a leaving group during synthesis bromine or iodine are preferred.

“1-4C-Haloalkyl”, which also can be defined as an alkyl moiety which issubstituted one or more times with halogen, is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms in which at least onehydrogen is substituted by a halogen atom. Examples are chloromethyl or2-bromoethyl. For a partially or completely fluorinated C1-C4-alkylgroup, the following partially or completely fluorinated groups areconsidered, for example: fluoromethyl, difluoromethyl, trifluoromethyl,fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl,tetrafluoroethyl, and penta-fluoroethyl, whereby fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, or1,1,1-trifluoroethyl are preferred. Partially or completely fluorinatedC1-C4-alkyl groups are considered to be encompassed by the term1-4C-haloalkyl.

“1-6C-Alkoxy” represents radicals, which in addition to the oxygen atom,contain a straight-chain or bran

ched alkyl radical having 1 to 6 carbon atoms. Examples which may bementioned are the hexoxy, pentoxy, butoxy, iso

butoxy, sec-butoxy, tert-butoxy, pro-poxy, isopropoxy, ethoxy andmethoxy radicals, preferred are methoxy, ethoxy, propoxy, isopropoxy.

“3-7C-Cycloalkyl” stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, preferably cyclopropyl.

“3-7C-Cycloalkyloxy” or “—O-(3-7C-cycloalkyl)” stands forcyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy, preferably cyclopropyloxy.

The term “heteroaryl” represents a monocyclic 5- or 6-membered aromaticheterocycle comprising without being restricted thereto, the 5-memberedheteroaryl radicals furyl, thienyl, pyrrolyl, oxa-zolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl(1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl(1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), as well asthe 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl, preferred 5- or 6-membered heteroaryl radicals are furanyl,thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. More preferred 5- or6-membered heteroaryl radicals are furan-2-yl, thien-2-yl, pyrrol-2-yl,thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl,pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-ylor pyridazin-3-yl.

The term “-(1-6C-alkyl)-heteroaryl” represents a heteroaryl radical asdefined above which is connected to the rest of the molecule via astraight or branched alkyl chain, preferably —(CH₂)-heteroaryl, or—(CH₂CH₂)-heteroaryl, whereby —(CH₂)-heteroaryl is particularlypreferred.

The term “Heteroaryloxy” or “—O-heteroaryl” represents the sameheteroaryl moieties as defined for the term heteroaryl whereby the ringis connected via an oxygen atom to the rest of the molecule.

The term “—O-(1-6C-alkyl)-heteroaryl” represents the same heterarylmoieties as defined for the term heteroaryl whereby the ring isconnected via a —O-(1-6Calkyl) spacer to the rest of the molecule.

The term “—O-(1-6C-alkyl) spacer” can vary in the sense of the inventionto have an alkylene chain having from 1-6, 1-5, 1-4, 1-3, 1-2 or 1carbon atoms which can be straight or branched where possible.

“3-7C-Heterocyclyl”, or “heterocyclyl” represents a mono- or polycyclic,preferably mono- or bicyclic, more preferably monocyclic, nonaromaticheterocyclic radical containing, 4 to 10, preferably 4 to 7, ring atoms,and up to 3, preferably up to 2, hetero atoms and/or hetero groups fromthe series consisting of N, O, S, SO, SO₂. The heterocyclyl radicals canbe saturated or partially unsaturated and, unless stated otherwise, maybe optionally substituted, one or more times, identically ordifferently, with a substituent selected from: 1-4C-alkyl,1-4C-haloalkyl, 1-4C-alkoxy, hydroxy, fluorine, whereby the 1-4C-alkylmay be optionally further substituted with hydroxy. Particularlypreferred heterocyclic radicals are 4- to 7-membered monocyclicsaturated heterocyclyl radicals having up to two hetero atoms from theseries consisting of O, N and S. The following may be mentioned by wayof example and by preference: oxetanyl, tetrahydrofuranyl, azetidinyl,3-hydroxyazetidinyl, 3-fluoroazetidinyl, 3,3-difluoroazetidinyl,pyrrolidinyl, 3-hydroxypyrrolidinyl, pyrrolinyl, piperidinyl,3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 3-fluoropiperidinyl,3,3-difluoropiperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl,piperazinyl, N-methyl-piperazinyl, N-(2-hydroxyethyl)-piperazinyl,morpholinyl, thiomorpholinyl, azepanyl, homopiperazinyl,N-methyl-homopiperazinyl.

The term “heterocyclyloxy” or —O-heterocyclyl” represents the sameheterocyclic moieties as defined for the term heterocyclyl whereby a Catom in the ring is connected via an oxygen atom to the rest of themolecule. Preferred heterocyclic moieties are either unsubstituted, ormay be optionally substituted on a ring nitrogen arom with a substituentselected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy.

The term “—O-(1-6C-alkyl)-heterocyclyl” represents the same heterocyclylmoieties as defined for the term heterocyclyl whereby the ring isconnected via a —O-(1-6Calkyl) spacer to the rest of the molecule. Inone aspect of the invention heterocyclic moieties containing one or morering nitrogen atom are preferably connected to the —O-(1-6-alkyl) spacervia one of the ring nitrogen atoms.

The term -(1-6C-alkyl)-heterocyclyl represents the same heterocyclylmoieties as defined for the term heterocyclyl s.o. whereby the ring isconnected via a -(1-6C-alkyl) spacer to the rest of the molecule.

The NH(CO)1-6C-alkyl or the NH(CO)R11 group includes for exampleNH(CO)CH3, NH(CO)C2H5, NH(CO)C3H7, NH(CO)CH(CH3)2.

The NHS(O)₂R11 group includes for example NHS(O)2CH3, NHS(O)2C2H5,NHS(O)2C3H7, NHS(O)2CH(CH3)2.

The NH(CO)NHR11 group includes for example NHC(O)NHCH3, NHC(O)NHC2H5.

The C(O)NR8R9 group includes, for example, C(O)NH2, C(O)N(H)CH3,C(O)N(CH3)2, C(O)N(H)CH2CH3, C(O)N(CH3)CH2CH3 or C(O)N(CH2CH3)2. In thecase of —NR8R9, when R8 and R9 together with the nitrogen atom to whichthey are attached form a 3-6C-heterocyclic ring, the term“3-6C-heterocyclic ring” is defined above.

The C(O)OR8 group includes for example C(O)OH, C(O)OCH3, C(O)OC2H5,C(O)C3H7, C(O)CH(CH3)2, C(O)OC4H9, C(O)OC5H11, C(O)OC6H13; forC(O)O(1-6Calkyl) the alkyl part may be straight or branched.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, one or more times, independentlyfrom one another at any possible position. When any variable occurs morethan one time in any constituent, each definition is independent.

In case of R1, R2 or R3 it is understood that the groups selected from1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl may beoptionally substituted, one or more times, identically or differently,with a substituent selected from: hydroxy, halogen, 1-6C-alkyl,1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10,—NHC(O)R11, —NHS(O)₂R11. Preferably the groups -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl.

The heteroarylic, or heterocyclic groups mentioned herein may besubstituted by their given substituents or parent molecular groups,unless otherwise noted, at any possible position, such as e.g. at anysubstitutable ring carbon or ring nitrogen atom. Analogously it is beingunderstood that it is possible for any heteroaryl or heterocyclyl groupto be attached to the rest of the molecule via any suitable atom ifchemically suitable. Unless otherwise noted, any heteroatom of aheteroarylic ring with unsatisfied valences mentioned herein is assumedto have the hydrogen atom(s) to satisfy the valences. Unless otherwisenoted, rings containing quaternizable amino- or imino-type ring nitrogenatoms (—N═) may be preferably not quaternized on these amino- orimino-type ring nitrogen atoms by the mentioned substituents or parentmolecular groups.

Salts of the compounds according to the invention include all inorganicand organic acid addition salts and salts with bases, especially allpharmaceutically acceptable inorganic and organic acid addition saltsand salts with bases, particularly all pharmaceutically acceptableinorganic and organic acid addition salts and salts with basescustomarily used in pharmacy.

One aspect of the invention are salts of the compounds according to theinvention including all inorganic and organic acid addition salts,especially all pharmaceutically acceptable inorganic and organic acidaddition salts, particularly all pharmaceutically acceptable inorganicand organic acid addition salts customarily used in pharmacy. Anotheraspect of the invention are the salts with di- and tricarboxylic acids.

Examples of acid addition salts include, but are not limited to,hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, salts ofsulfamic acid, formates, acetates, propionates, citrates, D-gluconates,benzoates, 2-(4-hydroxybenzoyl)-benzoates, butyrates, salicylates,sulfosalicylates, lactates, maleates, laurates, malates, fumarates,succinates, oxalates, malonates, pyruvates, acetoacetates, tartarates,stearates, benzensulfonates, toluenesulfonates, methanesulfonates,trifluoromethansulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates,naphthalinedisulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium,sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine,ammonium, salts optionally derived from NH3 or organic amines havingfrom 1 to 16 C-atoms such as e.g. ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylendiamine,N-methylpiperindine and and guanidinium salts.

The salts include water-insoluble and, particularly, water-solublesalts.

According to the person skilled in the art the compounds of formula (I)according to this invention as well as their salts may contain, e.g.when isolated in crystalline form, varying amounts of solvents. Includedwithin the scope of the invention are therefore all solvates and inparticular all hydrates of the compounds of formula (I) according tothis invention as well as all solvates and in particular all hydrates ofthe salts of the compounds of formula (I) according to this invention.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The term “(chemotherapeutic) anti-cancer agents”, includes but is notlimited to (i) alkylating/carbamylating agents such as Cyclophosphamid(Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®),Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinumderivatives like cis-platin (Platinex® BMS), oxaliplatin (Eloxatin®),satraplatin or carboplatin (Cabroplat® BMS); (iii) antimitoticagents/tubulin inhibitors such as vinca alkaloids (vincristine,vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®),Docetaxel (Taxotere®) and analogs as well as new formulations andconjugates thereof (like the nanoparticle formulation Abraxane® withpaclitaxel bound to albumin), epothilones such as Epothilone B(Patupilone®), Azaepothilone (Ixabepilone®) or Sagopilone; (iv)topoisomerase inhibitors such as anthracyclines (exemplified byDoxorubicin/Adriblastin®), epipodophyllotoxines (examplified byEtoposide/Etopophos®) and camptothecin and camptothecin analogs(exemplified by Irinotecan/Camptosar® or Topotecan/Hycamtin®); (v)pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine(Xeloda®), Arabinosylcytosine/Cytarabin (Alexan®) or Gemcitabine(Gemzar®); (vi) purin antagonists such as 6-mercaptopurine(Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and (vii) folicacid antagonists such as methotrexate (Farmitrexat®) or premetrexed(Alimta®).

The term “target specific anti-cancer agent”, includes but is notlimited to (i) kinase inhibitors such as e.g. Imatinib (Glivec®),ZD-1839/Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®),SU11248/Sunitinib (Sutent®), OSI-774/Erlotinib (Tarceva®), Dasatinib(Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib,Vandetanib (Zactima®) or Pazopanib; (ii) proteasome inhibitors such asPS-341/Bortezumib (Velcade®); (iii) histone deacetylase inhibitors likeSAHA (Zolinza®), PXD101, MS275, MGCD0103, Depsipeptide/FK228,NVP-LBH589, Valproic acid (VPA), CRA/PCI 24781, ITF2357, SB939 andbutyrates (iv) heat shock protein 90 inhibitors like17-allylaminogeldanamycin (17-AAG) or 17-dimethylaminogeldanamycin(17-DMAG); (v) vascular targeting agents (VTAs) like combretastin A4phosphate or AVE8062/AC7700 and anti-angiogenic drugs like the VEGFantibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinaseinhibitors such as PTK787/ZK222584 (Vatalanib®) or Vandetanib (Zactima®)or Pazopanib; (vi) monoclonal antibodies such as Trastuzumab(Herceptin®), Rituximab (MabThera/Rituxan®), Alemtuzumab (Campath®),Tositumomab (Bexxar®), C225/Cetuximab (Erbitux®), Avastin (see above) orPanitumumab (Vectibix®) as well as mutants and conjugates of monoclonalantibodies, e.g. Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomabtiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide basedtherapeutics like G-3139/Oblimersen (Genasense®) or the DNMT1 inhibitorMG98; (viii) Toll-like receptor/TLR 9 agonists like Promune®, TLR 7agonists like Imiquimod (Aldara®) or Isatoribine and analogues thereof,or TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA asTLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeuticssuch as anti-estrogens (e.g. Tamoxifen or Raloxifen), anti-androgens(e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin orTriptorelin) and aromatase inhibitors (e.g. Femara, Arimedex orAromasin).

Other “target specific anti-cancer agents” include bleomycin, retinoidssuch as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitorssuch as 5-Aza-2′-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine(Vidaza®), alanosine, cytokines such as interleukin-2, interferons suchas interferon α2 or interferon-γ, bcl2 antagonists (e.g. ABT-737 oranalogs), death receptor agonists, such as TRAIL, DR4/5 agonisticantibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists likemapatumumab or lexatumumab).

Specific examples of anti-cancer agents include, but are not limited 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab,alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine,anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine,basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119),belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel,calcium folinate, calcium levofolinate, capecitabine, carboplatin,carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab,chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine,clodronic acid, clofarabine, crisantaspase, cyclophosphamide,cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa,dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox,denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine,doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptiniumacetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol,epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin,oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetinbeta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide,picibanil, pirarubicin, plerixafor, plicamycin, poliglusam,polyestradiol phosphate, polysaccharide-K, porfimer sodium,pralatrexate, prednimustine, procarbazine, quinagolide, radium-223chloride, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib,risedronic acid, rituximab, romidepsin, romiplostim, sargramostim,sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib,streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tasonermin, teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin,temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin,thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trastuzumab, treosulfan,tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex,valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine,vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer,zoledronic acid, zorubicin.

A special aspect of the invention are combinations comprising at leastone compound according to claim 1 and at least one of the anti-cancerdrugs selected from Ancestim, atrigel-leuprolide, axitinib, BacillusCalmette-Guerin (BCG)-Tice, bosutinib, brentuximab vedotin, brivanibalaninate, Cervarix, cinacalcet hydrochloride, crizotinib, cytarabineocfosfate, diethylstilbestrol, doxorubicin eluting beads, enzastaurinhydrochloride, etoposide phosphate disodium salt, floxuridine,fludeoxyglucose (18F), Gardasil, histrelin acetate, icotinibhydrochloride, ingenol mebutate, interferon alfa-2A, interferon alfa-2b,interferon alfa-n1, interferon alfa, interferon gamma-n1, ketoconazole,leucovorin/UFT, leuprolide acetate depot, levothyroxine sodium,liposomal cytarabine, liposomal daunorubicin, liposomal doxorubicin,M-Vax, MDV-3100, midostaurin, minocycline hydrochloride, motesanibdiphosphate, muromonab-CD3, oblimersen sodium, octreotide acetate,omacetaxine mepesuccinate, ombrabulin hydrochloride, paclitaxelnanoparticles, paclitaxel poliglumex, PEG-liposomal doxorubicinhydrochloride, pilocarpine hydrochloride, pixantrone maleate, rapamycin,ridaforolimus, ruboxistaurin mesilate hydrate, ruxolitinib phosphate,thyrotropin alfa, trimetrexate glucuronate, VAL-083, vesnarinone,vincristine TCS, Virulizin, zotarolimus, AZD-8055, BEZ-235, BGT-226,BKM-120, CAL-101, CC-223, GDC-0980, GSK-2110183, GSK-2636771, OSI-027,perifosine, PF-04691502, pictrelisib, PX-866, triciribine phosphate,UCN-01, XL-147, XL-765, ARRY-162, AS-703026, E-6201, selumetinib,trametinib dimethyl sulfoxide.

The compounds according to the invention and their salts can exist inthe form of tautomers which are included in the embodiments of theinvention.

The compounds of the invention may, depending on their structure, existin different stereoisomeric forms. These forms include configurationalisomers or optionally conformational isomers (enantiomers and/ordiastereoisomers including those of atropisomers). The present inventiontherefore includes enantiomers, diastereoisomers as well as mixturesthereof. From those mixtures of enantiomers and/or disastereoisomerspure stereoisomeric forms can be isolated with methods known in the art,preferably methods of chromatography, especially high pressure liquidchromatography (HPLC) using achiral or chiral phase. The inventionfurther includes all mixtures of the stereoisomers mentioned aboveindependent of the ratio, including the racemates.

Some of the compounds and salts according to the invention may exist indifferent crystalline forms (polymorphs) which are within the scope ofthe invention.

Furthermore, derivatives of the compounds of formula (I) and the saltsthereof which are converted into a compound of formula (I) or a saltthereof in a biological system (bioprecursors or pro-drugs) are coveredby the invention. Said biological system is e.g. a mammalian organism,particularly a human subject. The bioprecursor is, for example,converted into the compound of formula (I) or a salt thereof bymetabolic processes.

The intermediates used for the synthesis of the compounds of claims 1-5as described below, as well as their use for the synthesis of thecompounds of claims 1-5, are one further aspect of the presentinvention. Preferred intermediates are the Intermediate Examples asdisclosed below.

The Compounds According to the Invention can be Prepared as Follows.

The compounds according to the invention can be prepared according tothe following scheme,

wherein X, Y, R1, R2, R3 and R4 have the meanings defined above, wherebyRx Ry is R6, or a protecting group; Hal is halogen, preferably M isMg-Hal, Zn-Hal, or Li.

Compounds of general formula (I) may be prepared from compounds ofgeneral formula (II). Rx may optionally be R6, or a protecting group, orother such precursor which requires further manipulation.

The use of amine protecting groups in organic synthesis is well known topersons practiced in the art. Amine protecting groups include, but arenot limited to:

-   -   carbamate protecting groups, including, but not limited to        methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate,        (Fmoc), tert-butyl carbamate (BOC), allyl carbamate, and benzyl        carbamate (CBZ) including benzyl carbamates substituted on the        phenyl ring,    -   amide protecting groups, including, but not limited to N-formyl        amide, and N-acetyl amide,    -   N-benzyl amine protecting groups, including N-benzyl amines        substituted on the phenyl ring.

When Rx and Ry of the compound of formula (I) are both hydrogen, Rx ofthe compound of formula (II) may be a protecting group and Ry of thecompound of formula (II) may be hydrogen, the same protecting group asRx, or a different protecting group, or Rx and Ry may combine to make acyclic imide protecting group, such as an N-phthaloyl protecting group.

An amine protecting group may be reacted with a suitable reagent toremove the protecting group and replace it with a hydrogen. Suchsuitable reagents include, but are not limited to:

-   -   acid reagents, include, but are not limited to hydrochloric        acid, acetic acid, trifluoroacetic acid, methanesulfonic acid,        trifluoromethanesulfonic acid, sulfuric acid, boron tribromide;        acid reagents may be used for the removal of tert-butyl        carbamate, N-formyl amide, or N-acetyl amide or protecting        groups.    -   base reagents, include, but are not limited to lithium        hydroxide, potassium hydroxide, sodium hydroxide, caesium        carbonate, ammonium hydroxide; base reagents may be used for the        removal of methyl carbamate, 9.fluorenyl carbamate, ethyl        carbamate, N-formyl amide, or N-acetyl amide protecting groups.    -   nucleophilic reagents, include, but are not limited to lithium        iodide, sodium iodide, potassium iodide, trimethylsilyl iodide,        hydrazine, nucleophilic reagents may be used for the removal of        benzyl carbamate, N-formyl amide, N-acetyl amide, or N-phthaloyl        protecting groups.    -   metal-mediated reagents, including, but are not limited to        nickel reagents, palladium reagents, platinum reagents may be        used for the removal of allyl carbamate protecting groups.    -   reduction reagents, include, but are not limited to sodium in        ammonia, or the combination of a hydrogen source, such as, but        not limited to hydrogen gas, formic acid, or a salt of formic        acid and a metal reagent, including, but not limited to a nickel        reagent, palladium reagent, platinum reagent; reduction reagents        may be used for the removal of 9-fluorenylmethyl carbamate,        benzyl carbamate, or N-benzyl amine protecting groups.

For example, Rx in compounds of general formula (II) may be a protectinggroup such as the Boc group, —CO(OtBu). Preparation of compounds ofgeneral formula (I) may thus be accomplished by use of an appropriatedeprotection reaction, such as in the case of a Boc group, acidicreaction conditions, for example, with a solution of 4M hydrochloricacid in dioxane or trifluoromethanesulfonic acid, in an appropriatesolvent, such as for example DCM and methanol, at ambient temperature.Further conditions to deprotect the Boc group, or further protectinggroups that may be suitable for use in blocking the amino functionalityin compounds of general formula (II), including their synthesis anddeprotection, are found, for example, in T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P.Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.Similarly, when Ry is not H, then Ry is a protecting group, such as forexample when Rx and Ry together form a cyclic protecting group such asfor example a phthalamide.

Furthermore, compounds of general formula (II) may contain functionalitythat may itself be further modified, thus allowing introduction of thedesired functionality in the R1, R2 or R3 groups. Such transformationsinclude oxidations, reductions, nucleophilic substitutions,electrophilic substitutions, radical reactions, or metal promotedreactions such as metal assisted cross-coupling reactions, such as forexample Suzuki, Stille, or Heck reactions, or the like. Similarly,compounds of general formula (I) may also be modified in this way toprovide further compounds according to the invention, providing thetransformations do not cause unwanted side reactions at the —NHR6 group.

Thus a further aspect of the invention is a process for the manufactureof compounds of general formula (I) according to claim 1 by reacting acompound of general formula (II)

whereinR1-R4 have the meaning as stated in claim 1 andRx,Ry are R6, or a protecting group,wherein transformation to a compound of general formula (I) isaccomplished by use of an appropriate deprotection reaction, whereby theprotecting groups as discussed above can be used.

Another aspect of the invention is a process as disclosed above wherebysubsequently of before the deprotection step, further modificationsallowing introduction of the desired functionality in the R1, R2 or R3groups can be performed.

Compounds of general formula (II) may be prepared from an intermediateketone of general formula (III) and a heterocyclic amine of generalformula (IV), by use of an appropriate cyclisation reaction. Forexample, compounds of general formula (II) may be prepared by reacting(III) and (IV) in an appropriate solvent, such as for example DMF orethanol, at elevated temperatures from 50° C. to 150° C. The use ofbasic additives such as a tertiary amine, for example triethylamine, maybe beneficial.

Compounds of general formula (IV) are either commercially available, maybe prepared using the methods described in the examples, may be preparedusing known methods, or may be prepared by analogous methods to thoseknown by the person skilled in the art.

Compounds of general formula (III) may be prepared from a ketone ofgeneral formula (V) by use of an appropriate halogenation reaction. Forexample in the case of halogen is Br, a suitable bromination reaction,such as for example by reacting a ketone of general formula (V) withpyridinium hydrobromide perbromide in a suitable solvent, such as THF,at suitable temperatures, such as for example from 0° C. to ambienttemperature.

Compounds of general formula (V) may be prepared from a compound ofgeneral formula (VI) using known methods, such as by addition of asuitable organometallic reagent (VII), in a suitable solvent, such asethereal solvents, for example THF, at low temperatures, for examplefrom −78° C. to −10° C., preferably from −30° C. to −10° C. Preferredorganometallic reagents are for example organomagnesium reagents inwhich M is —MgCl or —MgBr, more preferably —MgCl.

Compounds of general formula (VI) may be prepared from compounds ofgeneral formula (VIII) using known methods, such as by way of apalladium catalysed cyanation reaction, using a suitable catalyst suchas tetrakis(triphenylphosphine)palladium(0)[Pd(PPh₃)₄], a suitable cyanosource, such as zinc dicyanide, a suitable solvent, such as DMF, wherebydry DMF may be beneficial, and elevated temperatures, such as up to theboiling point of the solvent, preferably at 80° C.

Compounds of general formula (VIII) and (IX) are either commerciallyavailable, may be prepared using the methods described below, may beprepared using known methods, or may be prepared by analogous methods tothose known by the person skilled in the art.

One aspect of the invention are compounds of formula (II), especiallywherein Rx is the Boc group, —CO(OtBu) and Ry is hydrogen.

Another aspect of the invention is the process for the manufacture ofcompounds of general formula (I), characterized in that a compound offormula (II)

-   -   whereby R1-R4, X and Y have the meaning according to claim 1 and        Rx is R6 or a protecting group; Ry is hydrogen or a protecting        group, or Rx and Ry together, or Y and Rx together, may form a        cyclic protecting group, Hal is halogen,        is reacted with a solution of 4M hydrochloric acid in dioxane or        trifluoromethanesulfonic acid, in an appropriate solvent, such        as for example DCM and methanol, at ambient temperature forming        a compound of formula (I)

Thus another aspect of the invention is the use of intermediate offormula (II) for the preparation of compounds of formula (I).

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1-5 according to the Examples.

It is known to the person skilled in the art that, if there are a numberof reactive centers on a starting or intermediate compound, it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999,3rd Ed., or in P. Kocienski, Protecting Groups, Thieme MedicalPublishers, 2000.

The compounds according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such aschromatography on a suitable support material. Furthermore, reversephase preparative HPLC of compounds of the present invention whichpossess a sufficiently basic or acidic functionality, may result in theformation of a salt, such as, in the case of a compound of the presentinvention which is sufficiently basic, a trifluoroacetate or formatesalt for example, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt for example. Salts ofthis type can either be transformed into its free base or free acidform, respectively, by various methods known to the person skilled inthe art, or be used as salts in subsequent biological assays.Additionally, the drying process during the isolation of compounds ofthe present invention may not fully remove traces of cosolvents,especially such as formic acid or trifluoroacetic acid, to give solvatesor inclusion complexes. The person skilled in the art will recognisewhich solvates or inclusion complexes are acceptable to be used insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base, solvate, inclusion complex) of a compound ofthe present invention as isolated as described herein is not necessarilythe only form in which said compound can be applied to a biologicalassay in order to quantify the specific biological activity.

Salts of the compounds of formula (I) according to the invention can beobtained by dissolving the free compound in a suitable solvent (forexample a ketone such as acetone, methylethylketone ormethylisobutylketone, an ether such as diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol such asmethanol, ethanol or isopropanol) which contains the desired acid orbase, or to which the desired acid or base is then added. The acid orbase can be employed in salt preparation, depending on whether a mono-or polybasic acid or base is concerned and depending on which salt isdesired, in an equimolar quantitative ratio or one differing therefrom.The salts are obtained by filtering, reprecipitating, precipitating witha non-solvent for the salt or by evaporating the solvent. Salts obtainedcan be converted into the free compounds which, in turn, can beconverted into salts. In this manner, pharmaceutically unacceptablesalts, which can be obtained, for example, as process products in themanufacturing on an industrial scale, can be converted intopharmaceutically acceptable salts by processes known to the personskilled in the art.

Pure diastereomers and pure enantiomers of the compounds and saltsaccording to the invention can be obtained e.g. by asymmetric synthesis,by using chiral starting compounds in synthesis and by splitting upenantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to a person skilledin the art. Preferably, diastereomeric mixtures are separated bycrystallization, in particular fractional crystallization, orchromatography. Enantiomeric mixtures can be separated e.g. by formingdiastereomers with a chiral auxiliary agent, resolving the diastereomersobtained and removing the chiral auxiliary agent. As chiral auxiliaryagents, for example, chiral acids can be used to separate enantiomericbases such as e.g. mandelic acid and chiral bases can be used toseparate enantiomeric acids via formation of diastereomeric salts.Furthermore, diastereomeric derivatives such as diastereomeric esterscan be formed from enantiomeric mixtures of alcohols or enantiomericmixtures of acids, respectively, using chiral acids or chiral alcohols,respectively, as chiral auxiliary agents. Additionally, diastereomericcomplexes or diastereomeric clathrates may be used for separatingenantiomeric mixtures. Alternatively, enantiomeric mixtures can be splitup using chiral separating columns in chromatography. Another suitablemethod for the isolation of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1-5 according to the examples.

Optionally, compounds of the formula (I) can be converted into theirsalts, or, optionally, salts of the compounds of the formula (I) can beconverted into the free compounds. Corresponding processes are customaryfor the skilled person.

Optionally, compounds of the formula (I) can be converted into theirN-oxides. The N-oxide may also be introduced by way of an intermediate.N-oxides may be prepared by treating an appropriate precursor with anoxidizing agent, such as meta-chloroperbenzoic acid, in an appropriatesolvent, such as dichloromethane, at suitable temperatures, such as from0° C. to 40° C., whereby room temperature is generally preferred.Further corresponding processes for forming N-oxides are customary forthe skilled person.

Commercial Utility

The compounds of formula (I) and the stereoisomers of the compounds offormula (I) according to the invention are hereinafter referred to asthe compounds of the invention. In particular, the compounds of theinvention are pharmaceutically acceptable. The compounds according tothe invention have valuable pharmaceutical properties, which make themcommercially utilizable. In particular, they inhibit the Pi3K/Aktpathway and exhibit cellular activity. They are expected to becommercially applicable in the therapy of diseases (e.g. diseasesdependent on overactivated Pi3K/Akt). An abnormal activation of thePI3K/AKT pathway is an essential step towards the initiation andmaintenance of human tumors and thus its inhibition, for example withAKT inhibitors, is understood to be a valid approach for treatment ofhuman tumors. For a recent review see Garcia-Echeverria et al (Oncogene,2008, 27, 551-5526).

Cellular activity and analogous terms in the present invention is usedas known to persons skilled in the art, as an example, inhibition ofphosphorylation, inhibition of cellular proliferation, induction ofapoptosis or chemosensitization.

Chemosensitization and analogous terms in the present invention is usedas known to persons skilled in the art. These stimuli include, forexample, effectors of death receptor and survival pathways as well ascytotoxic/chemotherapeutic and targeted agents and finally radiationtherapy. Induction of apoptosis and analogous terms according to thepresent invention are used to identify a compound which excecutesprogrammed cell death in cells contacted with that compound or incombination with other compounds routinely used for therapy.

Apoptosis in the present invention is used as known to persons skilledin the art. Induction of apoptosis in cells contacted with the compoundof this invention might not necessarily be coupled with inhibition ofcell proliferation. Preferably, the inhibition of proliferation and/orinduction of apoptosis are specific to cells with aberrant cell growth.

Furthermore, the compounds according to the present invention inhibitprotein kinase activity in cells and tissues, causing a shift towardsdephosphorylated substrate proteins and as functional consequence, forexample the induction of apoptosis, cell cycle arrest and/orsensitization towards chemotherapeutic and target-specific cancer drugs.In a preferred embodiment, inhibition of the Pi3K/Akt pathway inducescellular effects as mentioned herein, alone, or in combination withstandard cytotoxic or targeted anti-cancer drugs.

Compounds according to the present invention exhibit anti-proliferativeand/or pro-apoptotic and/or chemosensitizing properties. Accordingly,the compounds of the present invention are useful for the treatment ofhyperproliferative disorders, in particular cancer. Therefore thecompounds of the present invention are useful to induce ananti-proliferative and/or pro-apoptotic and/or chemosensitizing effectin mammals, such as humans, suffering from a hyperproliferativedisorders, like cancer.

The invention further relates to a compound according to the inventionor a pharmaceutically acceptable salt thereof, for the treatment and/orprophylaxis, preferably treatment of (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, which includebenign neoplasia and malignant neoplasia, especially malignantneoplasia, including cancer and the tumor types as disclosed below.

Compounds according to the present invention exhibit anti-proliferativeand/or pro-apoptotic properties in mammals such as humans due toinhibition of metabolic activity of cancer cells which are able tosurvive despite of unfavourable growth conditions such as glucosedepletion, hypoxia or other chemo stress.

Thus, the compounds according to the present invention are useful fortreating, ameliorating or preventing diseases of benign or malignantbehaviour as described herein, such as e.g. for inhibiting cellularneoplasia.

Neoplasia in the present invention is used as known to persons skilledin the art. A benign neoplasia is described by hyperproliferation ofcells, incapable of forming an aggressive, metastasizing tumor in-vivo.In contrast, a malignant neoplasia is described by cells with multiplecellular and biochemical abnormalities, capable of forming a systemicdisease, for example forming tumor metastasis in distant organs.

The compounds according to the present invention can be preferably usedfor the treatment of malignant neoplasia. Examples of malignantneoplasia treatable with the compounds according to the presentinvention include solid and hematological tumors. Solid tumors can beexemplified by tumors of the breast, bladder, bone, brain, central andperipheral nervous system, colon, endocrine glands (e.g. thyroid andadrenal cortex), esophagus, endometrium, germ cells, head and neck,kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary,pancreas, prostate, rectum, renal, small intestine, soft tissue, testis,stomach, skin, ureter, vagina and vulva. Malignant neoplasias includeinherited cancers exemplified by Retinoblastoma and Wilms tumor. Inaddition, malignant neoplasias include primary tumors in said organs andcorresponding secondary tumors in distant organs (“tumor metastases”).Hematological tumors can be exemplified by aggressive and indolent formsof leukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

In another aspect of the invention the compounds according to thepresent invention can be preferably used for the treatment of breastcancer.

It is noted that a malignant neoplasia does not necessarily require theformation of metastases in distant organs. Certain tumors exertdevastating effects on the primary organ itself through their aggressivegrowth properties. These can lead to the destruction of the tissue andorgan structure finally resulting in failure of the assigned organfunction and death.

Drug resistance is of particular importance for the frequent failure ofstandard cancer therapeutics. This drug resistance is caused by variouscellular and molecular mechanisms. One aspect of drug resistance iscaused by constitutive activation of anti-apoptotic survival signalswith PKB/Akt as a key signalling kinase. Inhibition of the Pi3K/Aktpathway leads to a resensitization towards standard chemotherapeutic ortarget specific cancer therapeutics. As a consequence, the commercialapplicability of the compounds according to the present invention is notlimited to 1^(st) line treatment of cancer patients. In a preferredembodiment, cancer patients with resistance to cancer chemotherapeuticsor target specific anti-cancer drugs are also amenable for treatmentwith these compounds for e.g. 2^(nd) or 3^(rd) line treatment cycles. Inparticular, the compounds according to the present invention might beused in combination with standard chemotherapeutic or targeted drugs toresensitize tumors towards these agents.

Compounds according to the present invention are suitable for treatment,prevention or amelioration of the diseases of benign and malignantbehavior as described above, such as e.g. benign or malignant neoplasia,particularly cancer, especially a cancer that is sensitive to Pi3K/Aktpathway inhibition.

The present invention further includes a method for treating, preventingor ameliorating diseases, preferably treating mammals, including humans,which are suffering from one of the abovementioned conditions,illnesses, disorders or diseases. The method is characterized in that apharmacologically active and therapeutically effective and tolerableamount of one or more of the compounds according to the presentinvention is administered to the subject in need of such treatment.

The present invention further includes a method for treating, preventingor ameliorating diseases responsive to inhibition of the Pi3K/Aktpathway, in a mammal, including human, preferably treating diseasesresponsive to inhibition of the Pi3K/Akt pathway, in a mammal, includinghuman, comprising administering a pharmacologically active andtherapeutically effective and tolerable amount of one or more of thecompounds according to the present invention to said mammal.

The present invention further includes a method for inhibiting proteinkinase activity in cells comprising administering a pharmacologicallyactive and therapeutically effective and tolerable amount of one or moreof the compounds according to the present invention to a patient in needof such therapy.

The present invention further includes a method for treatinghyperproliferative diseases of benign or malignant behaviour and/ordisorders responsive to induction of apoptosis, such as e.g. cancer,particularly any of those cancer diseases described above, in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for inhibiting cellularhyperproliferation or arresting aberrant cell growth in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for inducing apoptosisin the therapy of benign or malignant neoplasia, particularly cancer,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to a subject in need of such therapy.

The present invention further includes a method for sensitizing towardschemotherapeutic or target-specific anti-cancer agents in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for treating benignand/or malignant neoplasia, especially malignant neoplasia, particularlycancer, in a mammal, including human, comprising administering apharmacologically active and therapeutically effective and tolerableamount of one or more of the compounds according to the presentinvention to said mammal.

The present invention further includes a method for treating solid andhematological tumors, whereby solid tumors can be exemplified by tumorsof the breast, bladder, bone, brain, central and peripheral nervoussystem, colon, endocrine glands (e.g. thyroid and adrenal cortex),esophagus, endometrium, germ cells, head and neck, kidney, liver, lung,larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum,renal, small intestine, soft tissue, testis, stomach, skin, ureter,vagina and vulva. Malignant neoplasias include inherited cancersexemplified by Retinoblastoma and Wilms tumor. In addition, malignantneoplasias include primary tumors in said organs and correspondingsecondary tumors in distant organs (“tumor metastases”). andhematological tumors can be exemplified by aggressive and indolent formsof leukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

A preferred aspect of the invention includes a method for treatingbreast cancer.

The present invention further relates to the use of the compounds forthe production of pharmaceutical compositions, which are employed forthe treatment, prophylaxis, and/or amelioration of one or more of theillnesses mentioned, preferably for the treatment of one or more of theillnesses mentioned.

The present invention further relates to the use of the compounds forthe manufacture of pharmaceutical compositions for treating, preventingor ameliorating, preferably treating hyperproliferative diseases and/ordisorders responsive to the induction of apoptosis, such as e.g. benignor malignant neoplasia, especially malignant neoplasia, in particularcancer, especially those cancer diseases and tumor types mentionedabove.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions for treating, preventing or ameliorating, preferablytreating benign or malignant neoplasia, especially malignant neoplasia,particularly cancer, such as e.g. any of those cancer diseases and tumortypes described above.

The invention further relates to a compound according to the inventionor a pharmaceutically acceptable salt thereof, for the treatment and/orprophylaxis, preferably treatment of (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, which includebenign neoplasia and malignant neoplasia, including cancer.

The invention further related to the use of a compound according to theinvention or a pharmaceutically acceptable salt thereof, for theproduction of a pharmaceutical composition for the treatment, preventionor amelioration of a disease mediated by a dysregulated function of asingle protein kinase or multiple protein kinases and/or disordersresponsive to the induction of apoptosis.

The invention further relates to a pharmaceutical composition,comprising a compound according to the invention or a pharmaceuticallyacceptable salt thereof, for the treatment and/or prophylaxis,preferably treatment of (hyper)proliferative diseases and/or disordersresponsive to induction of apoptosis, which include benign neoplasia andmalignant neoplasia, including cancer.

The present invention further relates to the use of compounds andpharmaceutically acceptable salts according to the present invention forthe manufacture of pharmaceutical compositions, which can be used forsensitizing towards chemotherapeutic and/or target specific anti-canceragents.

The present invention further relates to the use of compounds accordingto the present invention for the manufacture of pharmaceuticalcompositions, which can be used for sensitizing towards radiationtherapy of those diseases mentioned herein, particularly cancer.

The present invention further relates to the use of the compoundsaccording to the present invention for the manufacture of pharmaceuticalcompositions, which can be used in the treatment of diseases sensitiveto protein kinase inhibitor therapy and different to cellular neoplasia.These non-malignant diseases include, but are not limited to benignprostate hyperplasia, neurofibromatosis, dermatoses, and myelodysplasticsyndromes.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention anda pharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention andpharmaceutically acceptable auxiliaries and/or excipients.

In the sense of the invention auxiliaries, vehicles, excipients,diluents, carriers or adjuvants all mean additives which may be added tothe compound to obtain a pharmaceutically acceptable compositionsuitable for administration.

Thus the invention relates to a pharmaceutical compositions comprisingone or more of the compounds according to this invention and one or morepharmaceutically acceptable additives.

The pharmaceutical compositions according to this invention are preparedby processes, which are known per se and familiar to the person skilledin the art. As pharmaceutical compositions, the compounds of theinvention (=active compounds) are either employed as such, or preferablyin combination with suitable pharmaceutical additives, e.g. in the formof tablets, coated tablets, dragees, pills, cachets, granules, capsules,caplets, suppositories, patches (e.g. as TTS), emulsions (such as e.g.micro-emulsions or lipid emulsions), suspensions (such as e.g. nanosuspensions), gels, solubilisates or solutions (e.g. sterile solutions),or encapsuled in liposomes or as beta-cyclodextrine or beta-cyclodextrinderivative inclusion complexes or the like, the active compound contentadvantageously being between 0.1 and 95% and where, by the appropriatechoice of the additives, a pharmaceutical administration form (e.g. adelayed release form or an enteric form) exactly suited to the activecompound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound additives, for exampleantioxidants, dispersants, emulsifiers, preservatives, solubilizers(such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG 400, Tween 80,Captisol, Solutol HS15 or the like), colorants, complexing agents,permeation promoters, stabilizers, fillers, binders, thickeners,disintegrating agents, buffers, pH regulators (e.g. to obtain neutral,alkaline or acidic formulations), polymers, lubricants, coating agents,propellants, tonicity adjusting agents, surfactants, flavorings,sweeteners or dyes, can be used.

In particular additives of a type appropriate to the desired formulationand the desired mode of administration are used.

The administration of the compounds, pharmaceutical compositions orcombinations according to the invention may be performed in any of thegenerally accepted modes of administration available in the art.Illustrative examples of suitable modes of administration includeintravenous, oral, nasal, parenteral, topical, transdermal and rectaldelivery. Oral and intravenous deliveries are preferred.

Generally, the pharmaceutical compositions according to the inventioncan be administered such that the dose of the active compound is in therange customary for Pi3K/Akt pathway inhibitors. In particular, a dosein the range of from 0.01 to 4000 mg of the active compound per day ispreferred for an average adult patient having a body weight of 70 kg. Inthis respect, it is to be noted that the dose is dependent, for example,on the specific compound used, the species treated, age, body weight,general health, sex and diet of the subject treated, mode and time ofadministration, rate of excretion, severity of the disease to be treatedand drug combination.

The pharmaceutical composition can be administered in a single dose perday or in multiple subdoses, for example, 2 to 4 doses per day. A singledose unit of the pharmaceutical composition can contain e.g. from 0.01mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1500mg, most preferably 1 to 500 mg, of the active compound. Furthermore,the pharmaceutical composition can be adapted to weekly, monthly or evenmore infrequent administration, for example by using an implant, e.g. asubcutaneous or intramuscular implant, by using the active compound inform of a sparingly soluble salt or by using the active compound coupledto a polymer.

The present invention further relates to combinations comprising one ormore first active ingredients selected from the compounds of theinvention and one or more second active ingredients selected fromchemotherapeutic anti-cancer agents and target-specific anti-canceragents e.g. for treating, preventing or ameliorating diseases responsiveor sensitive to inhibition of the Pi3K/Akt pathway, such ashyperproliferative diseases of benign or malignant behaviour and/ordisorders responsive to the induction of apoptosis, more specificallybenign or malignant hyperplasia, particularly cancer, such as e.g. anyof those cancer diseases described above, especially breast cancer.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention assole active ingredient(s) and a pharmaceutically acceptable carrier ordiluent in the manufacture of pharmaceutical products for the treatmentand/or prophylaxis of the illnesses mentioned above.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention assole active ingredient(s) and a pharmaceutically acceptable additives inthe manufacture of pharmaceutical products for the treatment and/orprophylaxis of the illnesses mentioned above.

Depending upon the particular disease, to be treated or prevented,additional therapeutic active agents, which are normally administered totreat or prevent that disease, may optionally be coadministered with thecompounds according to this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease are known as appropriate for the disease beingtreated.

The anti-cancer agents mentioned herein above as combination partners ofthe compounds according to this invention are meant to includepharmaceutically acceptable derivatives thereof, such as e.g. theirpharmaceutically acceptable salts.

The person skilled in the art is aware of the total daily dosage(s) andadministration form(s) of the additional therapeutic agent(s)coadministered.

Said total daily dosage(s) can vary within a wide range depending fromthe agent combined.

In practising the present invention, the compounds according to thisinvention may be administered in combination therapy separately,sequentially, simultaneously, concurrently or chronologically staggered(such as e.g. as combined unit dosage forms, as separate unit dosageforms, as adjacent discrete unit dosage forms, as fixed or non-fixedcombinations, as kit-of-parts or as admixtures) with one or morestandard therapeutics (chemotherapeutic and/or target specificanti-cancer agents), in particular art-known anti-cancer agents, such asany of e.g. those mentioned above.

In this context, the present invention further relates to a combinationcomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known anti-cancer agent, such as e.g. one or more of thosementioned herein above, for separate, sequential, simultaneous,concurrent or chronologically staggered use in therapy, such as e.g. intherapy of any of those diseases mentioned herein.

The present invention further relates to a pharmaceutical compositioncomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known anti-cancer agent, such as e.g. one or more of thosementioned herein above, and, optionally, a pharmaceutically acceptablecarrier or diluent, for separate, sequential, simultaneous, concurrentor chronologically staggered use in therapy.

The present invention further relates to a combination productcomprising

a.) at least one compound according to this invention formulated with apharmaceutically acceptable carrier or diluent, andb.) at least one art-known anti-cancer agent, such as e.g. one or moreof those mentioned herein above, formulated with a pharmaceuticallyacceptable carrier or diluent.

The present invention further relates to a kit-of-parts comprising apreparation of a first active ingredient, which is a compound accordingto this invention, and a pharmaceutically acceptable carrier or diluent;a preparation of a second active ingredient, which is an art-knownanti-cancer agent, such as one of those mentioned above, and apharmaceutically acceptable carrier or diluent; for simultaneous,concurrent, sequential, separate or chronologically staggered use intherapy. Optionally, said kit comprises instructions for its use intherapy, e.g. to treat hyperproliferative diseases and diseasesresponsive or sensitive to inhibition of the Pi3K/Akt pathway, such ase.g. beningn or malignant neoplasia, particularly cancer, moreprecisely, any of those cancer diseases described above.

The present invention further relates to a combined preparationcomprising at least one compound according to this invention and atleast one art-known anti-cancer agent for simultaneous, concurrent,sequential or separate administration.

The present invention further relates to combinations, compositions,formulations, preparations or kits according to the present inventionhaving Pi3K/Akt pathway inhibitory activity.

In addition, the present invention further relates to a method fortreating in combination therapy hyperproliferative diseases and/ordisorders responsive to the induction of apoptosis, such as e.g. cancer,in a patient comprising administering a combination, composition,formulation, preparation or kit as described herein to said patient inneed thereof.

In addition, the present invention further relates to a method fortreating hyperproliferative diseases of benign or malignant behaviourand/or disorders responsive to the induction of apoptosis, such as e.g.cancer, in a patient comprising administering in combination therapyseparately, simultaneously, concurrently, sequentially orchronologically staggered a pharmaceutically active and therapeuticallyeffective and tolerable amount of a pharmaceutical composition, whichcomprises a compound according to this invention and a pharmaceuticallyacceptable carrier or diluent, and a pharmaceutically active andtherapeutically effective and tolerable amount of one or more art-knownanti-cancer agents, such as e.g. one or more of those mentioned herein,to said patient in need thereof.

In further addition, the present invention relates to a method fortreating, preventing or ameliorating hyperproliferative diseases and/ordisorders responsive to induction of apoptosis, such as e.g. benign ormalignant neoplasia, e.g. cancer, particularly any of those cancerdiseases mentioned herein, in a patient comprising administeringseparately, simultaneously, concurrently, sequentially orchronologically staggered to said patient in need thereof an amount of afirst active compound, which is a compound according to the presentinvention, and an amount of at least one second active compound, said atleast one second active compound being a standard therapeutic agent,particularly at least one art-known anti-cancer agent, such as e.g. oneor more of those chemotherapeutic and target-specific anti-cancer agentsmentioned herein, wherein the amounts of the first active compound andsaid second active compound result in a therapeutic effect.

In yet further addition, the present invention relates to a method fortreating, preventing or ameliorating, especially treatinghyperproliferative diseases and/or disorders responsive to induction ofapoptosis, such as e.g. benign or malignant neoplasia, especiallymalignanr neoplasia, e.g. cancer, particularly any of those cancerdiseases and tumor types mentioned herein, in a patient comprisingadministering a combination according to the present invention.

In addition, the present invention further relates to the use of acomposition, combination, formulation, preparation or kit according tothis invention in the manufacture of a pharmaceutical product, such ase.g. a commercial package or a medicament, for treating, preventing orameliorating, especially treating hyperproliferative diseases, and/ordisorders responsive to the induction of apoptosis, such as e.g.malignant or benign neoplasia, especially malignant neoplasia, such ase.g. cancer, particularly those diseases and tumor types mentionedherein.

The present invention further relates to a commercial package comprisingone or more compounds of the present invention together withinstructions for simultaneous, concurrent, sequential or separate usewith one or more chemotherapeutic and/or target specific anti-canceragents, such as e.g. any of those mentioned herein.

The present invention further relates to a commercial package consistingessentially of one or more compounds of the present invention as soleactive ingredient together with instructions for simultaneous,concurrent, sequential or separate use with one or more chemotherapeuticand/or target specific anti-cancer agents, such as e.g. any of thosementioned herein.

The present invention further relates to a commercial package comprisingone or more chemotherapeutic and/or target specific anti-cancer agents,such as e.g. any of those mentioned herein, together with instructionsfor simultaneous, concurrent, sequential or separate use with one ormore compounds according to the present invention.

The compositions, combinations, preparations, formulations, kits orpackages mentioned in the context of the combination therapy accordingto this invention may also include more than one of the compoundsaccording to this invention and/or more than one of the art-knownanti-cancer agents mentioned.

The first and second active ingredient of a combination or kit-of-partsaccording to this invention may be provided as separate formulations(i.e. independently of one another), which are subsequently broughttogether for simultaneous, concurrent, sequential, separate orchronologically staggered use in combination therapy; or packaged andpresented together as separate components of a combination pack forsimultaneous, concurrent, sequential, separate or chronologicallystaggered use in combination therapy.

The type of pharmaceutical formulation of the first and second activeingredient of a combination or kit-of-parts according to this inventioncan be according, i.e. both ingredients are formulated in separatetablets or capsules, or can be different, i.e. suited for differentadministration forms, such as e.g. one active ingredient is formulatedas tablet or capsule and the other is formulated for e.g. intravenousadministration.

The amounts of the first and second active ingredients of thecombinations, compositions or kits according to this invention maytogether comprise a therapeutically effective amount for the treatment,prophylaxis or amelioration of a hyperproliferative diseases and/or adisorder responsive to the induction of apoptosis, particularly one ofthose diseases mentioned herein, such as e.g. malignant or benignneoplasia, especially malignant neoplasia, e.g. cancer, like any ofthose cancer diseases and tumor types mentioned herein.

In addition, compounds according to the present invention can be used inthe pre- or post-surgical treatment of cancer.

In further addition, compounds of the present invention can be used incombination with radiation therapy.

As will be appreciated by persons skilled in the art, the invention isnot limited to the particular embodiments described herein, but coversall modifications of said embodiments that are within the spirit andscope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. Further compounds according to the invention, ofwhich the preparation is not explicitly described, can be prepared in ananalogous way.

The compounds, which are mentioned in the examples and the salts thereofrepresent preferred embodiments of the invention as well as a claimcovering all subcombinations of the residues of the compound of formula(I) as disclosed by the specific examples.

The term “according to” within the experimental section is used in thesense that the procedure referred to is to be used “analogously to”.

EXPERIMENTAL PART

The following table lists the abbreviations used in this paragraph andin the Intermediate Examples and Examples section as far as they are notexplained within the text body. NMR peak forms are stated as they appearin the spectra, possible higher order effects have not been considered.Chemical names were generated using ACD/Name Batch version 12.01 orusing AutoNom2000 as implemented in MDL ISIS Draw. In some casesgenerally accepted names of commercially available reagents were used inplace of AutoNom2000 generated names.

Abbreviation Meaning anh anhydrous boc t-Butoxycarbonyl br broad CIchemical ionisation d doublet dd doublet of doublet DAD diode arraydetector DCM dichloromethane DMF N,N-dimethylformamide EtOAc ethylacetate Eq. equivalent ESI electrospray (ES) ionization HPLC highperformance liquid chromatography LC-MS liquid chromatography massspectrometry m multiplet MeOH methanol MPLC medium performance liquidchromatography MS mass spectrometry n-BuLi n-Butyllithium NMR nuclearmagnetic resonance spectroscopy: chemical shifts (δ) are given in ppm.The chemical shifts were corrected by setting the DMSO signal to 2.50ppm using unless otherwise stated. PYBOP(benzotriazol-1-yloxy)tripyrrolidinophosphium hexafluorophosphate qquartet r.t. or rt room temperature RT retention time (as measuredeither with HPLC or UPLC) in minutes s singlet t triplet THFtetrahydrofuran UPLC ultra performance liquid chromatography

Other abbreviations have their meanings customary per se to the skilledperson. The various aspects of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

Examples UPLC-MS Standard Procedures

Analytical UPLC-MS was performed using UPLC-MS Method 1 unless otherwisestated. The masses (m/z) are reported from the positive modeelectrospray ionisation unless the negative mode is indicated (ES−).

Method 1:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.1% formic acid, eluent B:acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8ml/min; temperature: 60° C.; injection: 2 μl; DAD scan: 210-400 nm; ELSD

Method 2:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.2% ammonia, Eluent B: acetonitrile;gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;temperature: 60° C.; injection: 2 μl; DAD scan: 210-400 nm; ELSD

Method 3:

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.1% ammonia, eluent b: acetonitrile;gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;temperature: 60° C.; injection: 2 μl; DAD scan: 210-400 nm; ELSD

Method 4:

instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.2% ammonia, eluent B: acetonitrile;gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;temperature: 60° C.; injection: 2 μl; DAD scan: 210-400 nm; ELSD

INTERMEDIATE EXAMPLES Intermediate Example Int-1 tert-Butyl{1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

Step 1: tert-Butyl[1-(4-bromophenyl)cyclobutyl]carbamate

The free base of commercially available 1-(4-bromophenyl)cyclobutanaminehydrochloride [CAS 1193389-40-0](8.99 g, 34.24 mmol, 1.0 eq) wasprepared as follows: (8.99 g, 34.24 mmol, 1.0 eq) of the hydrochloridesalt was taken up in DCM and washed sequentially with aqueous sodiumbicarbonate and water and the organic portion was tried andconcentrated.

The crude amine was taken up in dry THF (120 mL) anddiisopropylethylamine (17.62 mL, 102.7 mmol, 3.0 eq) under nitrogen anda solution of di-tert-butyldicarbonate (8.22 g, 37.6 mmol, 1.1 eq) inTHF (20 mL) was added. The reaction was stirred at rt overnight. Themixture was partitioned between EtOAc and water and the extractedorganic phase was washed with brine and concentrated in vacuo to givethe title compound.

Alternatively, the title compound may be prepared by known methods, suchas those given in W02008/70041, in particular from commerciallyavailable (4-bromophenyl)acetonitrile.

Step 2: tert-Butyl[1-(4-cyanophenyl)cyclobutyl]carbamate

The title compound may be prepared from by known methods, such as thosegiven in W02008/70041, in particular fromtert-butyl[1-(4-bromophenyl)cyclobutyl]carbamate.

Alternatively, tert-butyl[1-(4-cyanophenyl)cyclobutyl]carbamate (CAS1032349-97-5) may be obtained commercially.

Step 3: tert-Butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate

The title compound may be prepared by known methods, such as those givenin W02008/70041, in particular fromtert-butyl[1-(4-cyanophenyl)cyclobutyl]carbamate.

Step 4: tert-Butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1A]

A mixture of tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate(5.0 g, 13.68 mmol, 1.0 eq) and pyridinium hydrobromide perbromide (4.38g, 13.68 mmol, 1.0 eq) in THF (78 mL) was stirred at 0° C. for 30minutes. The mixture was partitioned between EtOAc and water and theorganic phase washed respectively with aqueous sodium thiosulfatesolution and brine, dried, filtered through a silicone coated filterpaper and concentrated in vacuo to give the crude title compound (5.44g, 93% purity by UPLC-MS) which was used without further purification.

UPLC-MS (Method 4): RT=1.49 min; m/z=442.21 (ES−, M−H, M=C₂₃H₂₆⁷⁹BrNO₃).

Step 5: tert-Butyl{1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate[Int-1]

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was preparedin a manner analgous to that described for Intermediate Example Int-1-A(1.00 g, ˜80% purity, 1.87 mmol, 1.0 eq), 6-methylpyridazin-3-amine(CAS-Nr. 18591-82-7, 0.245 g, 2.24 mmol, 1.2 eq),N,N-diisopropylethylamine (0.33 mL, 1.87 mmol, 1.0 eq) and activated 3 Åmolecular sieves in isopropanol (5.7 mL) was heated for 7 hours underreflux. On cooling, the mixture was partitioned between DCM and water,stirred vigorously and filtered through a silicone coated filter paper.The filtrate was concentrated in vacuo. UPLC analysis of the crudeproduct indicated a purity of >90%. The crude product was used in thenext step without further purification.

UPLC-MS (Method 1): RT=1.41 min; m/z=455.89 (M+H).

Intermediate Example Int-2 tert-Butyl{1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)-carbamate that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A (1.85 g, ˜80% purity, 3.45 mmol, 1.0 eq),6-ethylpyridazin-3-ammonium chloride (CAS-Nr. 1178585-42-6, 0.660 g,4.14 mmol, 1.2 eq), N,N-diisopropylethylamine (1.20 mL, 6.89 mmol, 2.0eq) and activated 3 Å molecular sieves in isopropanol (10.5 mL) washeated for 12 hours under reflux. On cooling, the mixture waspartitioned between DCM and water, stirred vigorously and filteredthrough a silicone coated filter paper. The filtrate was concentrated invacuo. The crude mixture was purified via MPLC (Biotage Isolera; 100 gSNAP cartridge: hexane->hexane/ethyl acetate 2/1) to give 700 mg (43%yield) of the title compound in 69% purity (UPLC).

UPLC-MS (Method 3): RT=1.53 min; m/z=469.34 (M+H).

Intermediate Example Int-3 tert-Butyl(1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was preparedin a manner analgous to that described for Intermediate Example Int-1-A(1.85 g, ˜80% purity, 3.45 mmol, 1.0 eq),6-(trifluoromethyl)pyridazin-3-amine (CAS-Nr. 935777-24-5, 0.674 g, 4.14mmol, 1.2 eq), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq)and activated 3 Å molecular sieves in isopropanol (10.5 mL) was heatedfor 7 hours under reflux. On cooling, the mixture was partitionedbetween DCM and water, stirred vigorously and filtered through asilicone coated filter paper. The filtrate was concentrated in vacuo.The crude mixture was purified via MPLC (Biotage Isolera; 100 g SNAPcartridge: hexane->hexane/ethyl acetate 2/1) to give 680 mg (34% yield)of the title compound.

UPLC-MS (Method 3): RT=1.56 min; m/z=509.29 (M+H).

Intermediate Example Int-4 Ethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was preparedin a manner analgous to that described for Intermediate Example Int-1-A(3.3 g, ˜80% purity, 5.79 mmol), ethyl 6-aminopyridazine-3-carboxylate(CAS-Nr. 98548-01-7, 1 g, 5.57 mmol), N,N-diisopropylethylamine (0.97mL, 5.57 mmol) and activated 3 Å molecular sieves in isopropanol (30.4mL) was heated for 20 hours under reflux. On cooling the mixture waspartitioned between DCM and water, stirred vigorously and filteredthrough a silicone coated filter paper. The filtrate was concentrated invacuo, taken up in DCM and washed with dilute aqueous hydrochloric acid(1N) and brine, dried and concentrated in vacuo to give the crude titlecompound. Purification was achieved by chromatography on silica(gradient elution:Hexane:EtOAc 9:1 to Hexane:EtOAc 1:1) to give thetitle compound (2.80 g, 92% purity, 90% yield).

UPLC-MS (Method 3): RT=1.51 min; m/z=513.41 (M+H).

1H-NMR (400 MHz, d6-DMSO): δ=8.29 (d, 1H), 7.74 (d, 1H), 7.50-7.56 (m,8H), 7.31 (d, 2H), 4.33 (q, 2H), 2.28-2.39 (m, 4H), 1.88-1.99 (m, 1H),1.68-1.80 (m, 1H), 1.26-1.29 (m, 9H), 1.08 (br s, 3H).

Intermediate Example Int-5 tert-Butyl(1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was preparedin a manner analgous to that described for Intermediate Example Int-1-A(0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Registry No.7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74mL, 1.50 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h.On cooling, the mixture was filtered through a pad of Celite. The Celitewas washed with DCM, and the combined organics were washed with water,dried with sodium sulfate and concentrated under reduced pressure togive tert-butyl(1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.55 g, 78% yield).

UPLC-MS (Method 3): RT=1.52 min; m/z (rel intensity) 471 (95, (M+H)⁺),943 (100, 2M+H)⁺); ES− m/z (rel intensity) 469 (20, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H),1.65-1.81 br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H),6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50(d, J=9.6H, 1H).

Intermediate Example Int-6 tert-Butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was preparedin a manner analgous to that described for Intermediate Example Int-1-A(5.80 g, 13.1 mmol), 3-amino-4,6-dibromopyridazine (CAS Registry No.1206487-35-5, 3.96 g, 15.7 mmol, 1.2 eq), N,N-diisopropylethylamine (2.3mL, 13.0 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10g) in isopropanol (70 mL) was heated at the reflux temperature for 8 h.On cooling, the mixture was filtered through a pad of Celite. The Celitewas washed with DCM, and the combined organics were washed with water,dried with sodium sulfate and concentrated under reduced pressure. Theremaining material was purified using MPLC (Biotage Isolera; 100 g SNAPcartridge: 100% hexane 2.0 min., gradient to 75% hexane/25% EtOAc 2.5min., 75% hexane/25% EtOAc 4.5 min., gradient to 50% hexane/50% EtOAc 2min., 50% hexane/50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min.,100% EtOAc 5.7 min.) to give partially purified tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(2.65 g, ˜82% pure, 28% yield):

UPLC-MS (Method 3): RT=1.67 min; m/z (rel intensity) 597 (50, (M+H)⁺).

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H),1.65-1.81 (m, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H),6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50(d, J=9.6 Hz, 1H).

The following examples were prepared in a manner analogous toIntermediate Example Int-6 by reacting the appropriate amine withtert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate[prepared in a manner analgous to that described for IntermediateExample Int-1A]

Intermediate Example Structure/Name Characterization Int-6.1

  tert-Butyl {1-[4-(8-bromo-6- chloro-3-phenylimidazo[1,2-b]pyridazin-2- yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT =1.65 min; m/z (rel intensity) 553 (90, (M + H)⁺). Int-6.2

  tert-Butyl {1-[4-(6-chloro-3- phenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.54 min; m/z(rel intensity) 475 (100, (M + H)⁺), 949 (50, (2M + H)⁺). 1H-NMR(d6-DMSO): δ 0.99- 1.35 (br m, 9H), 1.65-1.80 (m, 1H), 1.86-2.01 (m,1H), 2.26- 2.39 m, 4H), 7.29 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.4, 1H),7.45- 7.60 (m, 7H), 8.25 (d, J = 9.4 Hz, 1H). Int-6.3

  tert-Butyl {1-[4-(6-amino-3- phenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.32 min; m/z(rel intensity) 456 (100, (M + H)⁺), 911 (50, (2M + H)⁺); ES-m/z (relintensity) 454 (100, (M − H)⁻), 911 (10, (2M − H)⁻). 1H-NMR (d6-DMSO): δ1.00- 1.35 (br m, 9H), 1.65-1.77 (m, 1H), 1.86-1.88 (m, 1H), 2.24- 2.38(m, 4H), 6.27 (s, 2H), 6.64 (d, J = 9.6 Hz, 1H), 7.29 (d, J = 8.3 Hz,2H), 7.37-7.50 (m, 7H), 7.74 (d, J = 9.4 Hz, 1H). Int-6.4

  tert-Butyl (1-{4-[6- (methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin- 2- yl]phenyl}cyclobutyl)carbamate UPLC-MS(Method 3): RT = 1.60 min; m/z (rel intensity) 487 (100, (M + H)⁺), 973(30, (2M + H)⁺). 1H-NMR (d6-DMSO): δ 1.00- 1.37 (br m, 9H), 1.68-1.79(m, 1H), 1.88-2.00 (m, 1H), 2.27- 2.38 (m, 4H), 2.43 (s, 3H), 7.18 (d, J= 9.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.40-7.49 (m, 3H), 7.52 (d, J =8.3 Hz, 2H), 7.57 (dm; J = 7.6 Hz, 2H), 7.98 (9.6 Hz, 1H). Int-6.5

  tert-Butyl {1-[4-(6-bromo-3- phenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.55 min; m/z(rel intensity) 519 (90, (M + H)⁺). 1H-NMR (d6-DMSO): δ 0.98- 1.32 (m,9H), 1.65-1.79 (m, 1H), 1.85-2.00 (m, 2H), 2.26- 2.39 (m, 4H), 7.29 (d,J = 8.5 Hz, 2H), 7.45 (d, J = 9.4 Hz, 1H), 7.47-7.57 (m, 7H), 8.14 (9.4Hz, 1H). Int-6.6

  tert-Butyl {1-[4-(8-amino-3- phenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.39 min; m/z(rel intensity) 456 (100, (M + H)⁺), 911 (20, (M + H)⁺); ES-m/z (relintensity) 454 (90, (M − H)⁻).

Intermediate Example Int-7 tert-Butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A solution of tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6 (0.10 g, 0.17 mmol in MeOH (3 mL) was cooledwith an ice bath and treated dropwise with sodium methoxide (0.5M inMeOH, 0.40 mL, 0.20 mmol, 1.2 eq). The resulting solution was allowed towarm to room temperature and was stirred at room temperature for 2 h,after which additional sodium methoxide was added (0.5M in methanol,0.40 mL, 0.20 mmol, 1.2 eq). The resulting solution was allowed to warmto room temperature and was stirred at room temperature for 2 h, afterwhich additional sodium methoxide was added (0.5M in MeOH, 0.40 mL, 0.20mmol, 1.2 eq). The resulting solution was added to ice water, and theaqueous mixture was extracted with DCM (3×25 mL). The combined organicphases were dried (Na₂SO₄ anh.) and concentrated under reduced pressureto give impure tert-butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(102 mg, ˜78% pure). This material was used without furtherpurification:

UPLC-MS (Method 3): RT=1.67 min; m/z (rel intensity) 549 (90, (M+H)⁺).

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.37 (br s, 6H),1.65-1.81 (br s, 1H), 1.85-2.00 (m, 1H), 2.25-2.38 m, 4H), 3.80 (s, 3H),6.92 (d, J=9.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50(d, J=9.6H, 1H).

The following examples were prepared in a manner analogous toIntermediate Example Int-7 by reacting the appropriate carbamate withsodium methoxide in methanol

Intermediate Example Structure/Name Characterization Int-7.1

  tert-Butyl (1-{4-[6-methoxy-3- phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2- yl]phenyl}cyclobutyl)carbamate UPLC-MS(Method 3): RT = 1.62 min; m/z (rel intensity) 548 (100, (M + H)⁺).Int-7.2

  tert-Butyl (1-{4-[6-methoxy-3- phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2- yl]phenyl}cyclobutyl)carbamate UPLC-MS(Method 3): RT = 1.60 min; m/z (rel intensity) 537 (100, (M + H)⁺);ES-m/z (rel intensity) 535 (100, (M − H)⁻). Int-7.3

  tert-Butyl {1-[4-(6-chloro-8- methoxy-3-phenylimidazo[1,2-b]pyridazin-2- yl)phenyl]cyclobutyllcarbamate UPLC-MS (Method 3): RT =1.53 min; m/z (rel intensity) 505 (100, (M + H)⁺); ES-m/z (relintensity) 503 (10, (M − H)⁻). 1H-NMR (d6-DMSO): δ 1.00- 1.34 (br m,9H), 1.66-1.79 (br s, 1H), 1.88-1.99 (m, 1 H), 2.26- 2.38 m, 4H), 6.95(s, 1 H), 7.27 (d, J = 8.6 Hz, 2H), 7.45-7.54 (m, 8H).

The following examples were prepared in a manner analogous toIntermediate Example Int-7 by reacting the appropriate carbamate withsodium ethoxide in ethanol

Intermediate Example Structure/Name Characterization Int-7.4

  tert-Butyl {1-[4-(6-bromo-8- ethoxy-3-phenylimidazo[1,2-b]pyridazin-2- yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT =1.61 min; m/z (rel intensity) 563 (90, (M + H)⁺), ES-m/z (rel intensity)561 (5, (M − H)⁻).

Intermediate Example Int-8 tert-Butyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

A solution of tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6 (0.66 g, 1.10 mmol) in MeOH (10 mL) wastreated dropwise with sodium methoxide (0.5M in MeOH, 11.0 mL, 5.51mmol, 5.0 eq) and the resulting mixture was stirred at room temperaturefor 12 h. The resulting solution was irradiated at 120° C. in amicrowave apparatus for 90 minutes. The resulting solution was added toice water, and the aqueous mixture was extracted with DCM (3×50 mL). Thecombined organic phases were dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; SNAP 10 g cartridge: 100% hexane 2.0 min., gradient to70% hexane/30% DCM 3 min., 70% hexane/30% DCM 3 min., gradient to 50%hexane/50% DCM 4 min., 50% hexane/50% DCM 3.5 min., gradient to 95%hexane/5% DCM 5.5 min., 95% hexane/5% DCM 5.5 min.) to give tert-butyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.19 g, 34%) followed by methyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.029 g, 5.4%).

tert-Butyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutyl)carbamate

UPLC-MS (Method 3): RT=1.53 min; m/z (rel intensity) 501 (50, (M+H)⁺).

1H-NMR (d6-DMSO): δ 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H),1.67-1.79 (br s, 1H), 1.87-1.98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s,3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.48 (m,5H), 7.52-7.56 (m, 2H).

Methyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutyl)carbamate

UPLC-MS (Method 3): RT=1.36 min; m/z (rel intensity) 459 (70, (M+H)⁺);ES− m/z (rel intensity) 457 (10, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.66-1.81 (m, 1H), 1.86-2.02 (br s, 1H), 2.35 (br t,J=7.3 Hz, 4H), 3.41 (br s, 3H), 3.76 (s, 3H), 4.20 (s, 3H), 6.41 (s,1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.51 (m, 5H), 7.51-7.57 (m, 2H), 7.87(br s, 1H).

Intermediate Example Int-9 Methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a solution of tert-butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7 (0.41 g, 0.75 mmol) in MeOH (10 mL) and THF(1 mL) in an autoclave was added1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.12 g,0.15 mmol, 0.20 equiv) and triethylamine (0.11 mL, 0.82 mmol, 1.1equiv.). The autoclave was flushed with CO (approximately 5 bar) threetimes, then was pressurized with CO (5.2 bar), stirred at roomtemperature 30 min., and briefly placed under reduced atmosphere (0.06bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.),heated to 110° C., and stirred at this temperature for 22 h. Theresulting solution was concentrated under reduced pressure. Theresulting material was crystallized from MeOH to give methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate(0.34 g, 85%):

UPLC-MS (Method 3): RT=1.46 min; m/z (rel intensity) 529 (70, (M+H)⁺);ES− m/z (rel intensity) 527 (5, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.18 (br s, 3H), 1.22-1.35 (br s, 6H),1.67-1.79 (br s, 1H), 1.87-1.98 (br s, 1H), 2.27-2.37 (m, 4H), 3.77 (s,3H), 4.20 (s, 3H), 6.41 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.38-7.48 (m,5H), 7.52-7.56 (m, 2H).

Intermediate Example Int-10 tert-Butyl{1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(Approach 1)

A mixture of methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described forIntermediate Example Int-9 (0.20 g, 0.38 mmol) in a solution of ammoniain MeOH (7N, 15 mL) and THF (1 mL) was irradiated in a microwaveapparatus at 130° C. for 90 min. The solids were collected by filtrationto give tert-butyl{1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.12 g, 63%):

UPLC-MS (Method 3): RT=1.30 min; m/z (rel intensity) 514 (70, (M+H)⁺);ES− m/z (rel intensity) 512 (90, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.20 (br s, 3H), 1.20-1.39 (br s, 6H),1.65-1.81 (br s, 1H), 1.86-2.02 (br m, 1H), 2.28-2.39 (m, 4H), 3.77 (s,3H), 4.13 (s, 3H), 7.15 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.41-7.55 (m,7H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

The following examples were prepared in a manner analogous toIntermediate Example Int-10 by reacting the appropriate carbamate with asolution of ammonia in MeOH:

Intermediate Example Structure/Name Characterization Int-10.1

  tert-Butyl (1-{4-[6-carbamoyl-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.29 min; m/z (rel intensity) 558 (100, (M + H)⁺);ES-m/z (rel intensity) 556 (100, (M − H)⁻).

The following examples were prepared in a manner analogous toIntermediate Example Int-10 by reacting the appropriate carbamate with asolution of methylamine in MeOH:

Intermediate Example Structure/Name Characterization Int-10.2

  tert-Butyl (1-{4-[8-ethoxy-6-(methylcarbamoyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.42 min; m/z (rel intensity) 542 (70, (M + H)⁺);ES-m/z (rel intensity) 540 (30, (M − H)⁻). Int-10.3

  tert-Butyl (1-{4-[8-methoxy-6-(methylcarbamoyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.35 min; m/z (rel intensity) 527 (70, (M + H)⁺);ES-m/z (rel intensity) 525 (20, (M − H)⁻).

Intermediate Example Int-11 tert-Butyl{1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a mixture of tert-butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7 (0.075 g, 0.14 mmol) and 5% palladium oncarbon (0.007 g) in DMF (1 mL) was added a solution of sodium formate(0.074 g, 1.09 mmol, 8.0 eq) in water (0.2 mL). The resulting mixturewas stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred atroom temperature for 1 h. The resulting solution was filtered through amembrane filter, and the solids were washed with MeOH (1 mL). Theresulting solution was diluted with EtOAc (25 mL), washed with water(2×25 mL), dried (Na₂SO₄ anh.) and concentrated under reduced pressureto give tert-butyl {1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate approximately75% purity (0.058 g, 90%):

UPLC-MS (Method 3): RT=1.44 min; m/z (rel intensity) 471 (100, (M+H)⁺);ES− m/z (rel intensity) 512 (90, (M−H)⁻).

The following examples were prepared in a manner analogous toIntermediate Example Int-11 by reacting the appropriate carbamate withsodium formate and a palladium catalyst

Intermediate Example Structure/Name Characterization Int-11.1

  tert-Butyl {1-[4-(3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.33 min; m/z(rel intensity) 441 (100, (M + H)⁺), 881 (50, (2M + H)⁺); ES-m/z (relintensity) 439 (100, (M − H)⁻), 879 (10, (2M − H)⁻). Int-11.2

  tert-Butyl (1-{4-[3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT =1.49 min; m/z (rel intensity) 507 (100, (M + H)⁺); ES-m/z (relintensity) 505 (100, (M − H)⁻). Int-11.3

  tert-Butyl {1-[4-(8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 0.83min; m/z (rel intensity) 457 (100, (M + H)⁺), 913 (70, (2M + H)⁺);ES-m/z (rel intensity) 455 (100, (M − H)⁻). Int-11.4

  tert-Butyl (1-{4-[8-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT= 1.49 min; m/z (rel intensity) 535 (100, (M + H)⁺); ES-m/z (relintensity) 533 (100, (M − H)⁻).

Intermediate Example Int-12 tert-Butyl{1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A mixture of tert-butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7 (0.30 g, 0.54 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol %)in 1,2-dimethoxyethane (4 mL) was stirred under an argon atmosphere for10 min, then was sequentially treated with K₂CO₃ (0.075 g, 0.54 mmol,1.0 eq), water (1.5 mL) and vinylboronic acid anhydride pyridine complex(prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54mmol, 1.0 eq). The resulting mixture was heated at the refluxtemperature for 16 h, then was added to water (15 mL). The resultingmixture was extracted with EtOAc (2×25 mL). The combined organic phaseswere washed with water (25 mL), dried (Na₂SO₄), and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min, gradient to80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min, gradient to50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min, gradient to100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert-butyl{1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.25 g, 92%):

UPLC-MS (Method 3): RT=1.55 min; m/z (rel intensity) 497 (100, (M+H)⁺);ES− m/z (rel intensity) 495 (10, (M−H)⁻).

1H-NMR (d6-DMSO): δ 0.80-1.37 (br m, 9H), 1.65-1.80 (br s, 1H),1.85-2.01 (br m, 1H), 2.27-2.37 (m, 4H), 4.02 (s, 3H), 5.63 (d, J=11.3Hz, 1H), 6.27 (d, J=17.7 Hz, 1H), 6.64 (dd, J=10.0, 17.7 Hz, 1H), 7.04(s, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.42-7.55 (m, 8H).

The following examples were prepared in a manner analogous toIntermediate Example Int-12 by reacting the appropriate carbamate withvinylboronic acid anhydride pyridine complex

Intermediate Example Structure/Name Characterization Int-12.1

  tert-Butyl {1-[4-(3-phenyl-6,8-divinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.71 min; m/z(rel intensity) 493 (100, (M + H)⁺), 985 (80, (2M + H)⁺); ES-m/z (relintensity) 491 (10, (M − H)⁻). Int-12.2

  tert-Butyl (1-{4-[3-phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.59 min; m/z (rel intensity) 533 (100, (M + H)⁺);ES-m/z (rel intensity) 531 (100, (M − H)⁻).

Intermediate Example Int-13 tert-Butyl{1-[4-(6-ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

A solution of tert-butyl{1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-12 (0.20 g, 0.40 mmol) in methanol (8 mL) washydrogenated using an H-Cube flow reactor (Pd/C cartridge). Theresulting solution was concentrated under reduced pressure to givetert-butyl{1-[4-(6-ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.20 g, 100%):

1H-NMR (d6-DMSO): δ 1.08-1.35 (br m, 9H), 1.19 (t, J=7.5 Hz, 3H),1.66-1.83 (br s, 1H), 1.85-2.03 (br m, 1H), 2.26-2.37 (m, 4H), 2.68 (q,J=7.5 Hz, 2H), 4.05 (s, 3H), 6.70 (s, 1H), 7.26 (d, J=8.5 Hz, 2H),7.41-7.53 (m, 8H).

The following examples were prepared in a manner analogous toIntermediate Example Int-13 by hydrogenation of the appropriatecarbamate using an H-Cube flow reactor

Intermediate Example Structure/Name Characterization Int-13.1

  tert-Butyl {1-[4-(6,8-diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.77 min; m/z(rel intensity) 497 (100, (M + H)⁺). Int-13.2

  tert-Butyl (1-{4-[6-ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.62 min; m/z (rel intensity) 535 (100, (M + H)⁺);ES-m/z (rel intensity) 533 (50, (M − H)⁻).

Intermediate Example Int-14 tert-Butyl(1-{4-[6-chloro-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl{1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7.1 (0.15 g, 0.27 mmol), 3-pyridineboronic acid(0.040 g, 0.33 mmol, 1.2 equiv.),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.022 g,0.03 mmol, 0.1 equiv.), Na₂CO₃ (0.086 g, 0.81 mmol, 3.0 equiv.), indioxane (2.9 mL) and water (0.4 mL) was bubbled with Ar, then placedunder an argon atmosphere and was irradiated in a microwave apparatus at105° C. for 90 min. The reaction mixture was then added to a mixture ofwater (10 mL), a saturated aqueous NH₄Cl solution (10 mL) and CH₂Cl₁₂(20 mL). The resulting mixture was stirred strongly for 30 minutes. Theorganic phase was separated, dried (Na₂SO₄ anh), and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to50% hexane/50% EtOAc 2.5 min, 50% hexane/50% EtOAc 3.5 min, gradient to100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give tert-butyl(1-{4-[6-chloro-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.046 g, 31%):

UPLC-MS (Method 3): RT=1.62 min; m/z (rel intensity) 552 (100, (M+H)⁺);ES− m/z (rel intensity) 550 (10, (M−H)⁻).

1H-NMR (d6-DMSO): δ 0.98-1.37 (br m, 9H), 1.66-1.81 (br s, 1H),1.85-2.00 (br m, 1H), 2.27-2.38 (m, 4H), 7.31 (d, J=8.5 Hz, 2H),7.49-7.58 (m, 7H), 7.64 (ddd, J=7.0, 4.7, 0.8 Hz, 1H), 7.85 (s, 1H),8.75 (ddd, J=4.9, 1.5 Hz, 1H), 8.81 (app dt, J=8.1, 1.9 Hz, 1H), 9.56(dd, J=2.3, 0.6 Hz, 1H).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate with[1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid

Intermediate Example Structure/Name Characterization Int-14.1

  tert-Butyl (1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method3): RT = 1.55 min; m/z (rel intensity) 541 (100, (M + H)⁺); ES-m/z (relintensity) 539 (80, (M − H)⁻).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate with[1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl]boronic acid

Intermediate Example Structure/Name Characterization Int-14.2

  tert-Butyl (1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT= 1.59 min; m/z (rel intensity) 541 (100, (M + H)⁺); ES-m/z (relintensity) 539 (50, (M − H)⁻). 1H-NMR (d6-DMSO): δ 1.00- 1.37 (br m,9H), 1.68-1.80 (br s, 1H), 1.88-2.00 (br m, 1H), 2.30- 2.38 (m, 3H),7.32 (d, J = 8.6 Hz, 2H), 7.49-7.56 (m, 5H), 7.61 (br d, J = 8.1 Hz,2H), 7.20-7.70 (m, 2H), 7.98 (br s, 1H).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate with(1-methyl-1H-pyrazol-5-yl)boronic acid

Intermediate Example Structure/Name Characterization Int-14.3

  tert-Butyl (1-{4-[6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl) carbamate UPLC-MS(Method 3): RT = 1.59 min; m/z (rel intensity) 555 (80, (M + H)⁺);ES-m/z (rel intensity) 553 (20, (M − H)⁻). 1H-NMR (d6-DMSO): δ 1.00-1.37 (br m, 9H), 1.65-1.80 (br s, 1H), 1.85-1.89 (br m, 1H), 2.26- 2.38(m, 4H), 4.05 (s, 3H), 6.92 (br s, 0.7 H), 7.30 (d, J = 8.5 Hz, 2H),7.49-7.57 (m, 8H), 7.64 (d, J = 2.0 Hz, 1H), 7.20-7.70 (m, 2H), 7.96 (s,0.3H).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate with(4-fluorophenyl)boronic acid

Intermediate Example Structure/Name Characterization Int-14.4

  tert-Butyl (1-{4-[6-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT= 1.64 min; m/z (rel intensity) 535 (100, (M + H)⁺); ES-m/z (relintensity) 533 (10, (M − H)⁻). Int-14.5

  tert-Butyl (1-{4-[6-chloro-8-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT= 1.77 min; m/z (rel intensity) 569 (100, (M + H)⁺).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate withcyclopropylboronic acid

Intermediate Example Structure/Name Characterization Int-14.6

  tert-Butyl {1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl] cyclobutyl}carbamate UPLC-MS(Method 3): RT = 1.70 min; m/z (rel intensity) 515 (100, (M + H)⁺).

The following examples were prepared in a manner analogous toIntermediate Example Int-14 by reacting the appropriate carbamate withpyridin-4-ylboronic acid

Intermediate Example Structure/Name Characterization Int-14.7

  tert-butyl (1-{4-[6-bromo-3-phenyl-8-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate UPLC-MS (Method 3): RT= 1.63 min; m/z (rel intensity) 596 (100, (M + H)⁺). 1H-NMR (d6-DMSO): δ1.00- 1.00-1.38 (m, 9H), 1.66-1.80 (br s, 1H), 1.85-2.00 (br m, 1H),2.28-2.38 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.47-7.58 (m, 8H), 7.94 (s,1H), 8.39 (dm, J = 6.2 Hz, 2H), 8.81 (dm, J = 6.0 Hz, 2H).

Intermediate Example Int-152-(4-{1-[(tert-Butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazin-8-yltrifluoromethanesulfonate

To a solution of tert-butyl{1-[4-(8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-11.3 (0.34 g, 0.75 mmol) and triethylamine(0.25 mL, 1.73 mmol, 2.3 equiv.) in DCM (3 mL) at −20° C. under argonwas added dropwise trifluoromethanesulfonic anhydride (0.15 mL, 0.90mmol, 1.2 equiv.). The reaction mixture was allowed to slowly warm toroom temperature, was stirred for 1 h, and was cooled to -10° C.Additional triethylamine (0.25 mL, 1.73 mmol, 2.3 equiv.) andtrifluoromethanesulfonic anhydride (0.15 mL, 0.90 mmol, 1.2 equiv.) wasadded. The mixture was allowed to warm to room temperature and wasstirred for 3 h. The mixture was treated with a 50% water/50% saturatedNaHCO₃ solution (10 mL). The aqueous mixture was extracted with DCM(3×10 mL), dried (Na₂SO₄ anh.), and concentrated under reduced pressure.The resulting material was purified using MPLC (Biotage Isolera; Snap 10g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 3.5min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 3.5 min, 100%EtOAc 4.5 min) to give2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yltrifluoromethanesulfonate (0.15 mg, 34%):

UPLC-MS (Method 3): RT=1.63 min; m/z (rel intensity) 588 (40, (M+H)⁺);ES− m/z (rel intensity) 587 (20, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.36 (br m, 9H), 1.68-1.80 (br s, 1H),1.88-2.00 (br m, 1H), 2.30-2.38 (m, 4H), 7.33 (d, J=8.6 Hz, 2H),7.47-7.57 (m, 7H), 7.62, (d, J=5.3 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H).

Intermediate Example Int-16 tert-Butyl{1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a solution of tert-butyl{1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6.1 (2.49 g, 4.50 mmol) in DMF (63 mL) wasadded potassium acetate (2.21 g, 22.5 mmol, 5.0 equiv.), and theresulting mixture was was irradiated in a microwave apparatus at 140° C.for 90 min. The resulting mixture was added to ice water (200 mL). Thewater mixture was extracted with a 4:1 DCM/isopropanol solution (4×50mL). The combined organic phases were dried (Na₂SO₄ anh.), andconcentrated under reduced pressure to give a brown oil (2.6 g). The oilwas triturated with MeOH to give tert-butyl{1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamateas a yellow powder (0.60 g, 27%):

UPLC-MS (Method 3): RT=0.93 min; m/z (rel intensity) 491 (100, (M+H)⁺),981 (80 (2M+H)⁺); ES− m/z (rel intensity) 489 (100, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.35 (br m, 9H), 1.65-1.80 (br s, 1H),1.86-1.99 (br m, 1H), 2.25-2.39 (m, 5H), 6.45 (s, 1H), 7.29 (d, J=8.7Hz, 2H), 7.42-7.52 (m, 8H).

Intermediate Example Int-17 tert-Butyl(1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

To a solution of tert-butyl{1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was in a manner analgous to that described for Intermediate ExampleInt-16 (1.90 g, 3.87 mmol) in DMF (50 mL) was added cesium carbonate(6.88 g, 11.6 mmol, 3.0 equiv.) and benzyl bromide (0.58 mL, 4.84 mmol,1.25 equiv.), and the resulting mixture was irradiated in a microwaveapparatus at 140° C. for 90 min. The resulting mixture stirred at roomtemperature for 16 h. The resulting mixture was added to ice water 100mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanolsolution (3×50 mL). The combined organic phases were dried (Na₂SO₄anh.), and concentrated under reduced pressure. The resulting oil wastriturated with ethanol to give tert-butyl(1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamateas a powder (0.93 g, 41%):

UPLC-MS (Method 3): RT=1.51 min; m/z (rel intensity) 581 (100, (M+H)⁺);ES− m/z (rel intensity) 579 (90, (M−H)⁻).

1H-NMR (d6-DMSO): δ 0.98-1.35 (br m, 9H), 1.64-1.78 (br s, 1H),1.84-2.00 (br m, 1H), 2.25-2.37 (m, 4H), 5.48 (s, 2H), 7.08 (s, 1H),7.26 (d, J=8.5 Hz, 2H), 7.37-7.57 (m, 13H).

Intermediate Example Int-18 Methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a solution of tert-butyl(1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-17 (0.91 g, 1.48 mmol) in MeOH (20 mL) and THF(2 mL) in an autoclave was added1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.24 g,0.30 mmol, 0.20 equiv) and triethylamine (0.23 mL, 1.63 mmol, 1.1equiv.). The autoclave was flushed with CO (approximately 5 bar) threetimes, then was pressurized with CO (5.2 bar), stirred at roomtemperature 30 min., and briefly placed under reduced atmosphere (0.06bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.),heated to 100° C., and stirred at this temperature for 18 h. Theresulting solution was concentrated under reduced pressure. Theresulting material was purified using MPLC (Biotage Isolera; Snap 25 gcartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 6.0min, 50% hexane/50% EtOAc 6.5 min, gradient to 10% hexane/90% EtOAc 6.0min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 26.7 min) to give methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate(0.34 g, 44%):

UPLC-MS (Method 3): RT=0.89 min; m/z (rel intensity) 515 (100, (M+H)⁺);ES− m/z (rel intensity) 513 (100, (M−H)⁻).

Intermediate Example Int-19 Methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

A mixture of methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was in a manner analgous to that described for Intermediate ExampleInt-18 (0.16 g, 0.32 mmol), ethyl iodide (0.50 mL, 0.63 mmol, 2.0equiv.) and cesuim carbonate (0.31 g, 0.94 mmol, 3.0 equiv.) in DMF (6mL) was stirred for 1 h at room temperature, followed by 3 h at 50° C.The reaction mixture was then added to ice water (20 mL). The aqueousmixture was extracted with a 4:1 DCM/isopropanol solution (2×25 mL). Thecombined organic phases were dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; Snap 10 g cartridge, 80% hexane/20% EtOAc 3.0 min,gradient to 55% hexane/45% EtOAc 2.0 min, 55%/45% EtOAc 3.0 min,gradient to 4% hexane/96% EtOAc 5.5 min, gradient to 100% EtOAc 0.5 min,100% EtOAc 7.2 min) to give methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate(0.072 g, 42%):

UPLC-MS (Method 3): RT=1.50 min; m/z (rel intensity) 543 (100, (M+H)⁺);ES− m/z (rel intensity) 541 (10, (M−H)⁻).

The following examples were prepared in a manner analogous toIntermediate Example Int-19 by reacting the appropriate phenol with2-methoxyethyl bromide

Intermediate Example Structure/Name Characterization Int-19.1

  Methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6- carboxylateUPLC-MS (Method 3): RT = 1.48 min; m/z (rel intensity) 573 (100, (M +H)⁺); ES- m/z (rel intensity) 571 (20, (M − H)⁻).

Intermediate Example Int-20 tert-Butyl(1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl{1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7.1 (0.78 g, 1.42 mmol),1H-imidazol-2-ylboronic acid (0.024 g, 2.13 mmol, 1.5 equiv.),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride CDM complex(0.12 g, 0.14 mmol, 0.1 equiv.) and cesium fluoride (0.65 g, 4.25 mmol,3.0 equiv.) in dimethoxymethane (12 mL) was bubbled with Ar, then placedunder an argon atmosphere in a sealed vial, and was heated at 100° C.for 3 days. The reaction mixture was then added to ice water (50 mL).The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution(4×50 mL). The combined organics were dried (Na₂SO₄ anh.) andconcentrated under reduced pressure. The resulting material was purifiedusing MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min,gradient to 50% hexane/20% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.5 min,gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min) to give tert-butyl(1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.28 g, 37%):

UPLC-MS (Method 3): RT=1.54 min; m/z (rel intensity) 541 (100, (M+H)⁺);ES− m/z (rel intensity) 539 (30, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.37 (br m, 9H), 1.68-1.80 (br s, 1H),1.88-2.00 (br m, 1H), 2.27-2.39 (m, 4H), 7.27 (app q, J=0.8 Hz, 1H),7.33 (d, J=8.6 Hz, 2H), 7.50-7.55 (m, 5H), 7.59 (d, J=8.6 Hz, 2H), 7.92(s, 1H), 8.81 (app t, J=1.4 Hz, 1H), 9.28-9.29 (m, 1H).

Intermediate Example Int-21 tert-Butyl{1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(Approach 2)

To a solution of tert-butyl{1-[4-(6-chloro-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7.3 (0.54 g, 1.00 mmol) in a solution ofammonia in MeOH (7N; 5.7 mL, 40 mmol, 40 equiv.) in an autoclave wasadded 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCMcomplex (0.16 g, 0.20 mmol, 0.20 equiv). The autoclave was flushed withCO (approximately 5 bar) three times, then was pressurized with CO (5.2bar), stirred at room temperature 30 min., and briefly placed underreduced atmosphere (0.06 bar). The autoclave was then pressurized withCO (5.9 bar at 20° C.), heated to 100° C., and stirred at thistemperature for 18 h. The resulting material was filtered andconcentrated under reduced pressure to give tert-butyl{1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.29 g, 57%):

UPLC-MS (Method 3): RT=1.29 min; m/z (rel intensity) 514 (70, (M+H)⁺);ES− m/z (rel intensity) 512 (100, (M−H)⁻).

Intermediate Example Int-22 Methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-8-carboxylate

To a solution of2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yltrifluoromethanesulfonate that was prepared in a manner analgous to thatdescribed for Intermediate Example Int-15 (0.15 g, 0.25 mmol) in MeOH(0.4 mL) and THF (0.04 mL) in an autoclave was added1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.040 g,0.050 mmol, 0.20 equiv) and triethylamine (0.040 mL, 0.27 mmol, 1.1equiv.). The autoclave was flushed with CO (approximately 5 bar) threetimes, then was pressurized with CO (5.2 bar), stirred at roomtemperature 30 min., and briefly placed under reduced atmosphere (0.06bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.),heated to 100° C., and stirred at this temperature for 18 h. Theresulting solution was concentrated under reduced pressure. Theresulting material was purified using MPLC (Biotage Isolera; Snap 10 gcartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 2.5min, gradient to 70% hexane/30% EtOAc 3.0 min, 70% hexane/30% EtOAc 2.5min, gradient to 50% hexane/50% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.0min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min) to give methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate(0.081 g, 63%):

UPLC-MS (Method 3): RT=1.46 min; m/z (rel intensity) 499 (100, (M+H)⁺),997 (70, (2M+H)⁺); ES− m/z (rel intensity) 497 (20, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.00-1.36 (br m, 9H), 1.65-1.81 (br s, 1H),1.86-2.02 (br m, 1H), 2.26-2.38 (m, 4H), 3.98 (s, 3H), 7.31 (d, J=8.5Hz, 2H), 7.46-7.58 (m, 8H), 7.64 (d, J=4.5 Hz, 1H), 8.58 (d, J=4.7 Hz,1H).

Intermediate Example Int-23 Dimethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6,8-dicarboxylate

To a solution of tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6 (0.51 g, 0.80 mmol) in MeOH (1.3 mL) and THF(0.13 mL) in an autoclave was added1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.13 g,0.16 mmol, 0.20 equiv) and triethylamine (0.12 mL, 0.88 mmol, 1.1equiv.). The autoclave was flushed with CO (approximately 5 bar) threetimes, then was pressurized with CO (5.2 bar), stirred at roomtemperature 30 min., and briefly placed under reduced atmosphere (0.06bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.),heated to 100° C., and stirred at this temperature for 18 h. Theresulting solution was concentrated under reduced pressure. Theresulting material was filtered and concentrated under reduced pressureto give dimethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxylate(0.45 g, 100%), which was used without further purification:

UPLC-MS (Method 3): RT=1.46 min; m/z (rel intensity) 557 (100, (M+H)⁺).

Intermediate Example Int-24 tert-Butyl{1-[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate(1) and2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide(2, Approach 1)

A solution of dimethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxylatethat was prepared in a manner analgous to that described forIntermediate Example Int-23 (0.45 g, 0.81 mmol) in a solution of ammoniain MeOH (7N, 11.5 mL) was irradiated in a microwave apparatus at 130° C.for 90 min. The resulting mixture was concentrated under reducedpressure. The resulting material was purified using MPLC (BiotageIsolera; Snap 25 g cartridge, 100% DCM 4.5 min, gradient to 95% DCM/5%MeOH 1.0 min, 95% DCM/5% MeOH 5.0 min, gradient to 90% DCM/10% MeOH 1.0min, 90% DCM/10% MeOH 8.1 min, gradient to 80% DCM/20% MeOH 2.0 min, 80%DCM/20% MeOH 8.2 min) to give tert-butyl {1-[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.34 g, 8%)followed by2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide(0.63 g, 18%).

tert-Butyl{1-[4-(6,8-dicarbamoyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(1)

UPLC-MS (Method 3): RT=1.28 min; m/z (rel intensity) 527 (100, (M+H)⁺);ES− m/z (rel intensity) 525 (60, (M−H)⁻).

2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide

UPLC-MS (Method 3): RT=1.02 min; m/z (rel intensity) 410 (100(M+H-17)+), 427 (70, (M+H)⁺), 853 (20, (2M+H)⁺); ES− m/z (rel intensity)425 (100, (M−H)⁻), 851 (10, (M−H)⁻).

Intermediate Example Int-25 tert-Butyl{1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutyl}carbamate

To a solution of tert-butyl{1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6.3 (0.10 g, 0.22 mmol) in DCM (4 mL) was addedpyridine (0.036 mL, 0.44 mmol, 2 equiv) and acetic anhydride (0.027 mL,0.29 mmol, 1.3 equiv). The reaction mixture was stirred for 24 h at roomtemperature, additional acetic anhydride (0.042 mL, 0.44 mmol, 2.0equiv) was added and the reaction mixture was stirred at roomtemperature for an additional 24 h. The resulting mixture wasconcentrated under reduced pressure to give tert-butyl{1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.11 g, 100%) which was used without further purification:

UPLC-MS (Method 3): RT=1.34 min; m/z (rel intensity) 498 (100, (M+H)⁺),995 (60, (M+H)⁺); ES− m/z (rel intensity) 496 (50, (M−H)⁻), 993 (10,(2M−H)⁻).

The following examples were prepared in a manner analogous toIntermediate Example Int-25 by reacting tert-butyl{1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(Intermediate Example Int-6.3) or tert-butyl{1-[4-(8-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(Intermediate Example Int-6.6) with the appropriate anhydride

Intermediate Example Structure/Name Characterization Int-25.1

  tert-Butyl [1-(4-{3-phenyl-6-[(trifluoroacetyl)amino]imidazo[1,2-b]pyridazin-2-yl}phenyl)cyclobutyl]carbamate This material was usedwithout characterization. Int-25.2

  tert-Butyl [1-(4-{6-[(methylsulfonyl)amino]-3-phenylimidazo[1,2-b]pyridazin-2-yl}phenyl)cyclobutyl]carbamate This material was usedwithout characterization. Int-25.3

  tert-Butyl {1-[4-(8-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate UPLC-MS (Method 3): RT = 1.47min; m/z (rel intensity) 498 (90, (M + H)⁺), 995 (20, (M + H)⁺); ES-m/z(rel intensity) 496 (90, (M − H)⁻).

Intermediate Example Int-26 tert-Butyl(1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

To a solution of tert-butyl(1-{4-[6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6.4 (0.10 g, 0.21 mmol) in chloroform (4 mL)was added meta-chloroperoxybenzoic acid (70% pure, 0.10 g, 0.42 mmol,2.0 equiv) portionwise. The resulting mixture was stirred at roomtemperature for 12 h, then was diluted with DCM (10 mL). The resultingmixture was washed with an aqueous NaOH solution (2N, 10 mL), dried(Na₂SO₄ anh.) and concentrated under reduced pressure to give tert-butyl(1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.12 g, 100%) which was used without further purification:

UPLC-MS (Method 3): RT=1.38 min; m/z (rel intensity) 519 (100, (M+H)⁺);ES− m/z (rel intensity) 517 (10, (M−H)⁻).

Intermediate Example Int-272-(4-{1-[(tert-Butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylicacid

To a solution of ethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described forIntermediate Example Int-4 (2.00 g, 3.90 mmol) in MeOH (50 mL) was addedan aqueous NaOH solution (10%, 10 mL). The resulting mixture was stirredat room temperature for 24 h, then was diluted with water (100 mL). Theresulting mixture was adjusted to pH 4 using an aqueous HCl solution(2N). The resulting crystals were collected, washed with water, anddried at 40° C. to give2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylicacid (1.50 g, 79%) which was used without further purification:

UPLC-MS (Method 3): RT=0.77 min; m/z (rel intensity) 485 (100, (M+H)⁺),969 (40, (2M+H)⁺); ES− m/z (rel intensity) 439 (60 (M−CO2H)⁻), 483 (100,(M−H)⁻), 967 (20, (M−H)⁻).

Intermediate Example Int-28 Methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate

A mixture of2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylicacid that was prepared in a manner analgous to that described forIntermediate Example Int-27 (0.075 g, 0.16 mmol), cesium carbonate (0.15g, 0.46 mmol, 3.0 equiv) and methyl iodide (0.020 mL, 0.31 mmol, 2.0equiv) in DMF (2 mL) was stirred at room temperature for 2 days, afterwhich additional methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) wasadded and the mixture was heated at 50° C. for 3 h. The resultingmixture was treated with water (25 mL). The aqueous mixture wasextracted with EtOAc (3×10 mL). The combined organics were dried (Na₂SO₄anh) and concentrated under reduced pressure to give methyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate(0.087 g, 113%) which was used without further purification:

UPLC-MS (Method 3): RT=1.46 min; m/z (rel intensity) 499 (100, (M+H)⁺),997 (60, (2M+H)).

Intermediate Example Int-29 tert-Butyl(1-{4-[6,8-bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6 (0.25 g, 0.42 mmol), (4-fluorophenyl)boronicacid (0.12 g, 0.84 mmol, 2.0 equiv.),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.034 g,0.042 mmol, 0.1 equiv.) and sodium carbonate (0.13 g, 1.25 mmol, 3.0equiv) in a mixture of water (0.6 mL) and dioxane (4.5 mL) wasirradiated in a microwave apparatus at 110° C. for 60 min. The resultingreaction mixture was added to water (25 mL). The aqueous mixture wasextracted with DCM (3×25 mL). The combined organic phases were washedwith an aqueous NaOH solution (2N), dried (Na₂SO₄ anh.) and concentratedunder reduced pressure to give impure tert-butyl(1-{4-[6,8-bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.39 g) which was used without further purification:

UPLC-MS (Method 3): RT=1.84 min; m/z (rel intensity) 629 (100, (M+H)⁺);ES− m/z (rel intensity) 673 (100, (M−H+HCO₂H)⁻).

Intermediate Example Int-30 tert-Butyl{1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenyl-imidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate

A mixture of2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylicacid that was prepared in a manner analgous to that described forIntermediate Example Int-27 (0.40 g, 0.82 mmol),O,N-dimethylhydroxylamine hydrochloride (0.12 g, 1.24 mmol, 1.5 equiv),PYBOP (0.54 g, 1.03 mmol, 1.25 equiv) and N,N-diisopropylethylamine (0.9mL, 4.95 mmol, 6.0 equiv) in DMF (15 mL) was stirred at room temperaturefor 21 h. The resulting mixture was added to ice water (50 mL). Theaqueous mixture was extracted with EtOAc (4×25 mL). The combined organicphases were sequentially washed with water (25 mL) and a saturatedaqueous NaCl solution (25 mL), dried (Na₂SO₄ anh.) and concentratedunder reduced pressure. The resulting brown oil (1.48 g) was purifiedusing MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min,gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min,gradient to 50% hexane/50% EtOAc 6.0 min, 50% hexane/50% EtOAc 6.5 min,gradient to 10% hexane/90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7min, 100% EtOAc 4.5 min) to give tert-butyl{1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.25 g, 57%):

UPLC-MS (Method 3): RT=1.40 min; m/z (rel intensity) 528 (100, (M+H)⁺);ES− m/z (rel intensity) 526 (10, (M−H+HCO₂H)⁻).

Intermediate Example Int-31 tert-Butyl(1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutyl)carbamate

To a solution of tert-butyl{1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-30 (0.25 g, 0.47 mmol) in THF (10 mL) at 0° C.under an argon atmosphere was added methylmagnesium chloride (3M in THF,0.40 mL, 1.19 mmol, 2.5 equiv) portionwise through a septum. Theresulting mixture was stirred at 0° C. and at room temperature for 5 h.Additional methylmagnesium chloride (3M in THF, 0.16 mL, 0.48 mmol, 1.0equiv) was added and the resulting mixture was stirred for 12 h. Theresulting mixture was added to a saturated aqueous ammonium chloridesolution (25 mL). The aqueous mixture was extracted with EtOAc (3×25mL). The combined organic phases were dried (Na₂SO₄ anh.) andconcentrated under reduced pressure. The resulting yellow oil (0.23 g)was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100%hexane 2.0 min, gradient to 50% hexane/50% EtOAc 2.0 min, 50% hexane/50%EtOAc 2.0 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 21.0 min) togive tert-butyl(1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate(0.053 g, 23%):

UPLC-MS (Method 3): RT=1.51 min; m/z (rel intensity) 483 (100, (M+H)⁺),965 (80, (2M+H)⁺); ES− m/z (rel intensity) 481 (10, (M−H)⁻).

Intermediate Example Int-32 tert-Butyl{1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

To a mixture of tert-butyl{1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-14.6 (0.136 g, 0.26 mmol) and 5% palladium oncarbon (0.026 g) in DMF (1 mL) was added a solution of sodium formate(0.18 g, 2.6 mmol, 10.0 eq) in water (0.4 mL). The resulting mixture wasstirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at roomtemperature for 1 h. The resulting solution was filtered through amembrane filter and concentrated under reduced pressure. The resultingmaterial was purified using MPLC (Biotage Isolera; Snap 10 g cartridge,100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 4.0 min, 80%hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.5 min, 70%hexane/30% EtOAc 9.6 min) to give tert-butyl{1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.12 g, 93%):

UPLC-MS (Method 3): RT=1.65 min; m/z (rel intensity) 483 (100, (M+H)⁺),965 (60, (M+H)⁺); ES− m/z (rel intensity) 481 (10, (M−H)⁻).

Intermediate Example Int-32 tert-Butyl{1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A](237 mg, ˜80% purity, 0.430 mmol, 1.0 eq),6-chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 67.2 mg,0.430 mmol, 1.0 eq) and N,N-diisopropylethylamine (70 μL, 0.430 mmol,1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. Oncooling the mixture was partitioned between DCM and water, stirredvigorously and filtered through a silicone coated filter paper. Thefiltrate was concentrated in vacuo. The crude mixture was purified viaMPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc9/1->hexane/EtOAc 3/2) to give 185 mg (78% yield) of the title compound.

UPLC-MS (Method 2): RT=1.68 min; m/z=504 (M+H)⁺.

Intermediate Example Int-33 Methyl6-amino-4,5-dimethylpyridazine-3-carboxylate

A mixture of 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr.76593-36-7,1.00 g, 6.35 mmol, 1.0 eq),[1,1,-bis-(diphenylphosphino)ferrocene]-palladium(II) dichloride (1.04g, 1.27 mmol, 0.2 eq) and triethylamine (973 μL, 6.98 mmol, 1.1 eq) wasplaced in 90 mL autoclave and dissolved in 11.3 mL MeOH/THF (10/1).

The autoclave was flushed with carbon monoxide (3×) and was thenpressurized with carbon monoxide to 9 bar. The reaction mixture wasstirred for 30 min at RT. The carbon monoxide was released and theautoclave was then degassed by the use of high vacuum. The autoclave wasagain pressurized to 9 bar with carbon monoxide and subsequently heatedto 100° C. In the course of the reaction, carbon monoxide consumptionwas observed (decrease of CO pressure). The autoclave was cooled to rt,and after release of carbon monoxide flushed with inert gas. Thereaction mixture was filtered through a small pad of Celite. The crudemixture was purified via MPLC (Biotage Isolera; 50 g SNAP cartridge:DCM->DCM/ethanol 95/5) to give 1.28 g (95% yield) of the title compoundin 85% purity (UPLC, area-%).

UPLC-MS (Method 2): RT=0.62 min; m/z=182 (M+H)⁺.

Intermediate Example Int-34 tert-Butyl{1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate

Step 1: 6-Methoxy-4,5-dimethylpyridazin-3-amine

6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17mmol, 1.0 eq) in 14.51 mL of a 25% solution (w/w) of sodium methylate inMeOH was heated for 1 h at 130° C. in a single mode microwave oven. Thereaction mixture was partitioned between DCM and water. The organicphase was washed with brine and dried (Na₂SO₄ anh.). Volatile componentswere removed by the use of a rotary evaporator and the crude mixture waspurified via MPLC (Biotage Isolera; 25 g SNAP NH2 cartridge:hexane->hexane/EtOAc 1/1) to give 250 mg (49% yield) of the titlecompound.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.98 (s, 3H), 2.00 (s, 3H), 5.49 (s,3H), NH ₂ not assigned.

Step 2: tert-Butyl{1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A](391 mg, ˜80% purity, 0.710 mmol, 1.0 eq),6-methoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manneranalgous to that described for Intermediate Example Int-34, Step 1, 108mg, 0.710 mmol, 1.0 eq) and N,N-diisopropylethylamine (140 μL, 0.780mmol, 1.1 eq) in butyronitrile (4.9 mL) was heated for 3 hours at 120°C. On cooling the reaction mixture was concentrated in vacuo. The crudemixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge:hexane/EtOAc 9/1->hexane/EtOAc 2/3) to give 105 mg (28% yield) of thetitle compound.

UPLC-MS (Method 2): RT=1.68 min; m/z=499 (M+H)+.

Intermediate Example Int-35 tert-Butyl(1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutyl)carbamate

Step 1: 4,5-Dimethyl-6-(methylsulfanyl)pyridazin-3-amine

6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 400 mg, 2.54mmol, 1.0 eq) and sodium methanethiolate (196 mg, 2.79 mmol, 1.1 eq) in10.4 mL ethanol were heated for 1 h to 130° C. in a single modemicrowave oven. The reaction mixture was partitioned between DCM andwater. The organic phase was washed with brine and dried with sodiumsulfate. The resulting mixture was filtered through a Whatman filter andthe volatile components were removed in vacuo. The crude mixture waspurified via MPLC (Biotage Isolera; 50 g SNAP cartridge: DCM/ethanol95/5->DCM/ethanol 4/1) to give 182 mg (21% yield) of the title compoundin 50% purity (UPLC, area-%).

UPLC-MS (Method 2): RT=0.76 min; m/z=170 (M+H)⁺.

Step 2: tert-Butyl(1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenyl-imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A](540 mg, ˜80% purity, 0.970 mmol, 1.0 eq),4,5-dimethyl-6-(methylsulfanyl)-pyridazin-3-amine (that was prepared ina manner analgous to that described for Intermediate Example Int-35,Step 1, 181 mg, ˜50% purity, 1.07 mmol, 1.1 eq) andN,N-diisopropylethylamine (170 μL, 0.970 mmol, 1.1 eq) in butyronitrile(4.7 mL) was heated for 4 hours at 125° C. On cooling the reactionmixture was concentrated in vacuo. The crude mixture was purified viareversed phase preparative HPLC to give 105 mg (19% yield) of the titlecompound.

UPLC-MS (Method 2): RT=1.74 min; m/z=516 (M+H)⁺.

Intermediate Example Int-36 tert-Butyl{1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate

Step 1: 6-Ethoxy-4,5-dimethylpyridazin-3-amine

6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17mmol, 1.0 eq) and sodium ethanolate in ethanol (16 mL, 21 w/w-%, 53.9mmol, 17 eq) were heated for 2 h to 130° C. in a single mode microwaveoven. The reaction mixture was partitioned between DCM and water. Theorganic phase was washed with brine and dried with sodium sulfate. Theresulting mixture was filtered through a Whatman filter and the volatilecomponents were removed in vacuo. The crude mixture was purified viaMPLC (Biotage Isolera; 28 g NH2-cartridge: hexane->hexane/EtOAc 1/1) togive 267 mg (50% yield) of the title compound.

UPLC-MS (Method 2): RT=0.78 min; m/z=168 (M+H)⁺.

Step 2: tert-Butyl{1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutyl}carbamate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A](300 mg, ˜80% purity, 0.540 mmol, 1.0 eq),6-ethoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manneranalgous to that described for Intermediate Example Int-36, Step 1, 124mg, ˜80% purity, 0,590 mmol, 1.1 eq) and N,N-diisopropylethylamine (100μL, 0.590 mmol, 1.1 eq) in butyronitrile (3.3 mL) was heated for 3.5hours at 125° C. On cooling the reaction mixture was concentrated invacuo. The crude mixture was purified via preparative MPLC (BiotageIsolera; 50 g SNAP-cartridge: hexane/EtOAc 9/1->hexane/EtOAc 1/1) togive 220 mg (70% yield) of the title compound.

UPLC-MS (Method 2): RT=1.74 min; m/z=514 (M+H)⁺.

Example 11-[4-(6-Methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutan-amine

To a mixture of tert-butyl{1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-1 (200 mg, 0.440 mmol, 1.0 eq) in DCM (2.2 mL)and methanol (1.8 mL) was added a solution of 4M hydrogen chloride indioxane (2.2 mL, 8.80 mmol, 20.0 eq) and the mixture was stirred forovernight at rt. The mixture was poured onto ice, made alkaline withaqueous sodium hydroxide (2N) and extracted with DCM. The combinedorganic phases were washed with brine, dried and concentrated in vacuo.Purification was achieved by crystallization from diisopropyl ether. Theresulting solid was filtered and dried under high vacuum overnight togive 130 mg (83% yield) of the title compound.

UPLC-MS (Method 2): RT=1.20 min; m/z=355.68 (M+H).

1H-NMR (400 MHz, MeOD): δ [ppm]=1.96 (m, 1H), 2.24 (m, 1H), 2.54-2.64(m, 2H), 2.67 (s, 3H), 2.70-2.84 (m, 2H), 7.49-7.65 (m, 7H), 7.66-7.71(m, 2H), 7.80 (d, 1H), 8.32 (d, 1H), NH ₂ not assigned.

Example 21-[4-(6-Ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine

To a mixture of tert-butyl{1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-2 (300 mg, 0.608 mmol, 1.0 eq) in DCM (3.9 mL)and MeOH (2.5 mL) was added a solution of 4M hydrogen chloride indioxane (3.0 mL, 12.2 mmol, 20.0 eq) and the mixture was stirred forovernight at rt. The mixture was poured onto ice, made alkaline withaqueous sodium hydroxide (2N) and extracted with DCM. The combinedorganic phases were washed with brine, dried and concentrated in vacuo.Purification was achieved by crystallization from diisopropyl ether. Theresulting solid was filtered and dried under high vacuum overnight togive 119 mg (52% yield) of the title compound.

UPLC-MS (Method 4): RT=1.37 min; m/z=369.29 (M+H).

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.18 (t, 3H), 1.59 (m, 1H), 1.82-2.20(m, 5H), 2.25-2.39 (m, 2H), 2.73 (q, 2H), 7.20 (d, 1H), 7.31-7.38 (m,2H), 7.39-7.56 (m, 7H), 8.06 (d, 1H).

Example 31-{4-[3-Phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}-cyclobutanamine

To a mixture of tert-butyl(1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-3 (680 mg, 1.177 mmol, 1.0 eq) in DCM (7.6 mL)and methanol (4.8 mL) was added a solution of 4M hydrogen chloride indioxane (5.9 mL, 23.5 mmol, 20.0 eq) and the mixture was stirred forovernight at rt. The mixture was poured onto ice, made alkaline withaqueous sodium hydroxide (2N) and extracted with EtOAc (3×). Thecombined organic phases were washed with brine, dried and concentratedin vacuo. Purification was achieved by crystallization from diisopropylether. The resulting solid was filtered and dried under high vacuumovernight to give 440 mg (92% yield) of the title compound.

UPLC-MS (Method 4): RT=1.40 min; m/z=393.58 (M−NH2)⁺.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.60 (m, 1H), 1.85-2.25 (m, 5H),2.27-2.39 (m, 2H), 7.40 (d, 2H), 7.45-7.61 (m, 7H), 7.67 (d, 1H), 8.46(d, 1H).

Example 4 Ethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

To a mixture of ethyl2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described forIntermediate Example Int-4 (0.96 g, 1.87 mmol) in DCM (12.0 mL) andmethanol (7.6 mL) was added a solution of 4M hydrochloric acid indioxane (9.4 mL) and the mixture was stirred for 2 hours at rt. Themixture was poured onto ice, made alkaline with aqueous sodium hydroxide(2N) and extracted with DCM. The combined organic phases were washedwith brine, dried and concentrated in vacuo. The reaction was repeatedusing 2.5 g of the carbamate and the crude product from both reactionswere combined. Purification was achieved by chromatography on silica(gradient elution: 95:5 DCM:ethanol to 8:2 DCM:ethanol) to give twofractions of the title compound (0.8 g, 88% purity & 1.6 g, 93% purity).

UPLC-MS (Method 3): RT=0.97 min; m/z=413.44 (M+H).

Example 52-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide

A mixture of ethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described for Example 4,(1.00 g, 93% purity) and ammonia (17.3 mL of a 7M solution in methanol)was heated at 130° C. under microwave irradiation for 5 hours. Thevolatile components were removed by distillation under reduced pressure.Crystallization from methanol/diisopropyl ether gave the title compound(672 mg, 72% yield) as a yellow solid.

UPLC-MS (Method 2): RT=0.99 min; m/z=366.59 (M−NH₂).

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=8.26 (d, 1H), 7.87 (br s, 1H), 7.69(d, 1H), 7.61-7.63 (m, 2H), 7.55-7.57 (m, 3H), 7.44-7.53 (m, 3H), 7.39(d, 2H), 2.29-2.36 (m, 2H), 1.89-2.06 (m, 5H), 1.55-1.65 (m, 1H).

Example 61-[4-(6-Methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutan-amine

To a mixture of tert-butyl(1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-5 (550 mg, 1.17 mmol) in DCM (7.5 mL) and MeOH(0.8 mL) was added a 4M hydrogen chloride solution in dioxane (5.8 mL,23.4 mmol, 20.0 eq), and the resulting mixture was stirred at roomtemperature for 12 h. The resulting mixture was added to ice water, madealkaline with aqueous sodium hydroxide (2N), and extracted with EtOAc(3×25 mL). The combined organic phases were washed, dried (Na₂SO₄ anh.)and concentrated under reduced pressure. The resulting material waspurified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% DCM 3.5min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min.,gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 4.5 min.) to give1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(379 mg, 83% yield):

UPLC-MS (Method 3): RT=1.28 min; m/z (rel intensity) 371 (95, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.52-1.66 (m, 1H), 1.87-2.08 (m, 3H), 2.05-2.28(br m, 2H), 2.28-2.38 (m, 2H), 3.79 (s, 3H), 6.91 (d, J=9.6 Hz, 1H),7.35 (d, J=8.7 Hz, 2H), 7.40-7.53 (m, 3H), 7.49 (d, 8.5 Hz, 2H), 7.57(ddm, J=8.3, 1.5 Hz, 2H), 8.05 (d, J=9.6 Hz).

Example 71-[4-(6-Bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of tert-butyl(1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7 (100 mg, 0.18 mmol) in dioxane (4 mL) wasadded trifluoromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 eq), andthe resulting mixture was stirred at room temperature for 12 h. Theresulting mixture was added to ice water, made alkaline with aqueoussodium hydroxide (2N), and extracted with EtOAc (3×25 mL). The combinedorganic phases were washed, dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90%DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20%MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give material (40 mg) whichwas further purified by preparative HPLC (Waters Autopurification Systemequipped with pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424and SQD 3001 using a Xselect CSH C18 5 uM 100×30 mm column; 60% waterwith 1% HCO₂H/40% methanol 1 min., gradient to 10% water with 1%HCO₂H/90% methanol 7 min) to give1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(15 mg, 18%):

UPLC-MS (Method 3): RT=1.32 min; m/z (rel intensity) 432 (95,(M+H-17)+), 449 (60, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.55-1.65 (m, 1H), 1.90-2.00 (m, 1H), 2.03-2.11(m, 2H), 2.30-2.38 (m, 2H), 4.10 (s, 3H), 7.03 (s, 1H), 7.36 (d, J=8.6Hz, 2H), 7.45-7.54 (m, 7H).

Example 82-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylicacid

To a solution of ethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described for Example 4(260 mg, 0.63 mmol) in methanol (1.5 mL) was added aqueous sodiumhydroxide (3N, 0.63 mL, 1.89 mmol, 3.0 eq), and the resulting mixturewas stirred at 50° C. for 1 h. The resulting mixture was added to icewater, made slightly acidic with aqueous citric acid (10%), and washedwith DCM (3×25 mL). The aqueous phase was made alkaline and adjusted topH4 using hydrochloric acid (1N). The precipitate was collected byfiltration, washed with water and dried under high vacuum overnight toyield 218 mg (88% yield) of the title compound.

UPLC-MS (Method 1): RT=0.71 min; m/z (ES_(neg))=383 (M−H)⁻.

1H-NMR (DMSO-d₆, +1 drop TFA-d): δ [ppm]1.77 (m, 1H), 1.10 (m, 1H),2.40-2.64 (m, 4H, partially obscured by solvent signal), 7.40-7.60 (d,7H), 7.68 (d, 2H), 7.78 (d, 1H), 8.30 (d, 1H), 8.50 (m, 1H).

Example 91-[4-(6,8-Dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of tert-butyl(1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-7 (0.18 g, 0.37 mmol) in methanol (2.2 mL) andDCM (3.5 mL) was added hydrogen chloride (4M in dioxane, 1.8 mL, 7.3mmol, 20.0 eq), and the resulting mixture was stirred at roomtemperature for 20 h. The resulting mixture was added to ice water, madealkaline with aqueous sodium hydroxide (2N), and extracted with EtOAc(3×25 mL). The combined organic phases were dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting material was purifiedusing MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% DCM 6.0 min.,gradient to 95% DCM/5% MeOH 4 min., 95% DCM/5% MeOH 5 min., gradient to90% DCM/10% MeOH 3.5 min.) to give1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.11 g, 79%):

UPLC-MS (Method 3): RT=1.31 min; m/z (rel intensity) 384 (100,(M+H-17)+), 401 (70, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.52-1.65 (m, 1H), 1.88-2.07 (m, 5H), 2.27-2.38(m, 2H), 3.77 (s, 3H), 4.03 (s, 3H), 6.40 (s, 1H), 7.34 (d, J=8.5 Hz,2H), 7.39-7.50 (m, 5H), 7.51-7.56 (m, 2H).

Example 102-[4-(1-Aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide

To a solution of2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylamidethat was prepared in a manner analgous to that described forIntermediate Example Int-10 (0.095 g, 0.18 mmol) in MeOH (1 mL) and DCM(1.8 mL) was added hydrogen chloride (4M in dioxane, 0.9 mL, 3.7 mmol,20.0 eq), and the resulting mixture was stirred at room temperature for3 days. The resulting mixture was added to ice water, made alkaline withaqueous sodium hydroxide (2N), and extracted with EtOAc (3×50 mL). Thecombined organic phases were dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using preparativeHPLC (Waters Autopurification System equipped with pump 254, SampleManager 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using a Xselect CSHC18 5 uM 100×30 mm column; 60% water with 1% HCO₂H/40% MeOH 1 min.,gradient to 10% water with 1% HCO₂H/90% MeOH 7 min) to give2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide(0.020 g, 31%):

UPLC-MS (Method 3): RT=1.03 min; m/z (rel intensity) 397 (100,(M+H-17)+), 414 (50, (M+H)⁺); ES− m/z (rel intensity) 412 (70, (M−H)⁻).

1H-NMR (DMSO-d₆): δ [ppm]1.53-1.66 (m, 1H), 1.89-2.07 (m, 5H), 2.12 (brs, 2H). 2.28-2.38 (m, 2H), 4.07 (s, 3H), 7.15 (s, 1H), 7.37 (d, J=8.5Hz, 2H), 7.42-7.56 (m, 6H), 7.56-7.62 (m, 2H), 7.82 (br s, 1H).

Example 111-[4-(8-Methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclo-butanamine

To a solution of tert-butyl{1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-11 (0.055 g, 0.12 mmol) in a mixture of MeOH(0.7 mL) and DCM (1.1 mL) was added a concentrated aqueous HCl solution(approximately 12N, 0.6 mL). The resulting mixture was stirred at roomtemperature for 60 h, then poured onto ice water (15 mL). The resultingmixture was made basic with a 2N NaOH solution, then was extracted withEtOAc (3×20 mL). The combined organic phases were dried (Na₂SO₄ anh.)and concentrated under reduced pressure. The resulting oil (34 mg) waspurified using preparative HPLC (Agilent Prep 1200 equipped with 2× PrepPump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mmcolumn; gradient from 70% water with 0.2% NH₃/30% CH₃CN to 40% waterwith 0.2% NH₃/60% CH₃CN over 17.5 min, gradient from 40% water with 0.2%NH₃/60% CH₃CN to 100% CH₃CN over 2.5 min) to give1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.021 g, 48% yield): UPLC-MS (Method 3): RT=1.18 min; m/z (relintensity) 371 (30, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.52-1.65 (m, 1H), 1.87-2.13 (m, 5H), 2.12 (brs, 2H). 2.28-2.37 (m, 2H), 4.06 (s, 3H), 6.73 (d, J=5.7 Hz 1H), 7.35 (d,J=8.7 Hz, 2H), 7.43-7.50 (m, 5H), 7.53, (d, J=8.7 Hz, 2H).

The following examples were prepared in a manner analogous to Example 11by reacting the corresponding carmabate intermediates with aconcentrated aqueous HCl solution

Example Structure/Name Characterization 12

  Methyl 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate UPLC-MS (Method 3): RT =1.21 min; m/z (rel intensity) 429 (70, (M + H)⁺). 1H-NMR (DMSO-d₆): δ[ppm] 1.55-1.64 (m, 1H), 1.89-2.05 (m, 4H), 2.12 (br s, 2H), 2.30- 2.36(m, 2H), 3.85 (s, 3H), 4.15 (s, 3H), 7.18 (s, 1H), 7.36 (d, J = 8.6 Hz,2H), 7.46-7.55 (m, 7H). 13

  1-[4-(6-Ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT = 1.34 min;m/z (rel intensity) 399 (50, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.19(t, J = 7.5 Hz, 3H), 1.53- 1.65 (m, 1H), 1.87-2.10 (m, 5H), 2.27-2.37(m, 2H), 2.68 (q, J = 7.5 Hz, 2H), 4.05 (s, 3H), 6.70 (s, 1H), 7.34 (d,J = 8.5 Hz, 2H), 7.42-7.52 (m, 7H). 14

  1-{4-[6-Methoxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT =1.41 min; m/z (rel intensity) 431 (100, (M + H − 17)⁺), 448 (70, (M +H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.55-1.65 (m, 1H), 1.87-2.20 (m, 5H),2.29-2.39 (m, 2H), 3.85 (s, 3H), 7.35 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H),7.43-7.54 (m, 5H), 7.58-7.63 (m, 3H), 8.70- 8.77 (m, 2H), 9.50 (dm, J =2.2 Hz, 1H). 15

  1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl} cyclobutanamine HCl salt UPLC-MS(Method 3): RT = 1.34 min; m/z (rel intensity) 420 (100, (M + H − 17)⁺),437 (50, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.56-1.64 (m, 1H),1.89-2.12 (m, 4H), 2.33-2.38 (m, 3H), 3.78 (s, 3H), 7.23 (s, 1H), 7.36-7.41 (m, 3H), 7.44-7.50 (m, 4H), 7.54-7.62 (m, 4H), 9.22 (s, 1H),8.60-8.93 (br m, 2H). 16

  1-[4-(6,8-Diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT = 1.52 min; m/z (relintensity) 380 (90, (M + H − 17)⁺), 397 (100, (M + H)⁺). 1H-NMR (CD₃OD):δ [ppm] 1.33 (t, J = 7.6 Hz, 3H), 1.47 (t, J = 7.6 Hz, 3H), 1.76-1.82(m, 1H), 2.06-2.15 (m, 2H), 2.24- 2.32 (m, 2H), 2.57-2.63 (m, 2H), 2.85(q, J = 7.6 Hz, 2H), 3.14 (qd, J = 7.6, 1.0 Hz, 2H), 7.08 (s, 1H),7.42-7.49 (m, 5H), 7.55 (dd, J = 7.9, 1.3 Hz), 7.61 (d, J = 8.5 Hz, 2H).

Example 171-[4-(6-Chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutan-amine

To a solution of tert-butyl{1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6.2 (0.075 g, 0.15 mmol) in MeOH (0.65 mL) andDCM (1.0 mL) was added hydrogen chloride (4M in dioxane, 0.8 mL, 3.2mmol, 20.0 eq), and the resulting mixture was stirred at roomtemperature for 19 h. The resulting mixture was added to ice water (50mL), made alkaline with aqueous sodium hydroxide (2N), and extractedwith EtOAc (2×50 mL). The combined organic phases were dried (Na₂SO₄anh.) and concentrated under reduced pressure. The resulting materialwas recrystallized using diisopropyl ether to give1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.040 g, 68%):

UPLC-MS (Method 3): RT=1.32 min; m/z (rel intensity) 358 (100,(M+H-17)+), 375 (60, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.52-1.65 (m, 1H), 1.87-2.07 (m, 3H), 2.16 (brs, 2H). 2.27-2.37 (m, 2H), 7.35-7.40 (m, 3H), 7.48-7.56 (m, 7H), 8.25(d, J=9.4 Hz, 1H).

Example 181-[4-(8-Methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of tert-butyl{1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-12 (40 mg, 0.081 mmol) in dioxane (1.7 mL) wasadded trifluoromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 eq), andthe resulting mixture was stirred at room temperature for 12 h. Theresulting mixture was added to ice water, made alkaline with aqueoussodium hydroxide (2N), and extracted with EtOAc (3×25 mL). The combinedorganic phases were washed, dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; 10 g SNAP cartridge: 100% DCM 3.0 min., gradient to95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 2.5 min., gradient to 90%DCM/10% MeOH 3 min., 90% DCM/10% MeOH 3.5 min.) to give1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.022 g, 70%):

UPLC-MS (Method 3): RT=1.32 min; m/z (rel intensity) 380 (95,(M+H-17)+), 397 (70, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.54-1.64 (m, 1H), 1.89-2.10 (m, 5H), 2.28-2.36(m, 2H), 4.11 (s, 3H), 5.63 (d, J=11.4 Hz, 1H), 6.27 (d, J=17.7 Hz, 1H),6.64 (dd, J=17.7, 11.1 Hz, 1H), 7.06 (s, 1H), 7.35 (d, J=8.3 Hz, 2H),7.42-7.53 (m, 8H).

The following examples were prepared in a manner analogous to Example 18by reacting the corresponding carbamate intermediates withtrifluoromethanesulfonic acid

Example Structure/Name Characterization 19

  1-{4-[6-Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl} cyclobutanamine UPLC-MS (Method 3):RT = 1.39 min; m/z (rel intensity) 424 (90 (M + H − 17)⁺), 441 (100,(M + H)⁺); ES-m/z (rel intensity) 438 (100, (M − H)⁻). 1H-NMR (DMSO-d₆):δ [ppm] 1.55-1.66 (m, 1H), 1.90-1.99 (m, 1H), 2.00-2.09 (m, 2H),2.31-2.39 (m, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.49-7.56 (m, 5H), 7.62 (d,J = 8.3 Hz, 2H), 7.74-7.76 (m, 2H), 7.97 (d, J = 2 Hz, 1H). 20

  1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT =1.39 min; m/z (rel intensity) 416 (90 (M + H − 17)⁺), 433 (100, (M +H)⁺), 865 (10 (2M + H)⁺); ES- m/z (rel intensity) 431 (100, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.53-1.67 (m, 1H), 1.88-2.21 (m, 5H),2.29-2.39 (m, 3H), 5.66 (d, J = 11.1 Hz, 1H), 6.24 (d, J = 17.7 Hz, 1H),6.76 (dd, J = 17.7, 11.1 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.47-7.57(m, 5H), 7.63 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 1.5 Hz, 1H), 7.93 (br s,1H), 8.03 (s, 1H). 21

  1-{4-[6-Ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT =1.42 min; m/z (rel intensity) 418 (90 (M + H − 17)⁺), 435 (100, (M +H)⁺), 891 (10 (2M + Na)⁺); ES-m/z (rel intensity) 433 (100, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.23 (t, J = 7.6 Hz, 3H), 1.55- 1.65 (m, 1H),1.88-1.98 (m, 1H), 2.00-2.20 (m, 3H), 2.31- 2.38 (m, 2H), 2.79 (q, J =7.6 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.43-7.57 (m, 5H), 7.68 (s, 1H),7.69 (br s, 1H)), 7.91 (br s, 1H). 22

  2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide UPLC-MS (Method 3): RT =1.17 min; m/z (rel intensity) 425 (100 (M + H − 17)⁺), 442 (70, (M +H)⁺), 883 (30 (2M + H)⁺); ES-m/z (rel intensity) 440 (60, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.47 (t, J = 7.1 Hz, 3H), 1.55- 1.65 (m, 1H),1.89-2.06 (m, 6H), 2.28-2.37 (m, 2H), 2.77 (d, J = 4.6 Hz, 3H), 4.45 (q,J = 7.1 Hz, 2H), 7.10 (s, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.43-7.53 (m,6H), 7.55-7.59 (m, 2H), 8.09 (q, J = 4.8 Hz, 1H). 23

  1-{4-[6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} cyclobutanamine UPLC-MS(Method 3): RT = 1.39 min; m/z (rel intensity) 438 (100 (M + H − 17)⁺),455 (40, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.70-1.82 (m, 1H),2.03-2.14 (m, 1H), 2.51-2.59 (m, 2H, partially obscured by solventsignal), 4.06 (s, 3H), 7.01 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.3 Hz,2H), 7.51-7.57 (m, 5H), 7.58 (s, 1H), 7.64-7.68 (m, 3H). 24

  1-{4-[6-Chloro-8-(1H-imidazol-2-yl)-3-phenyl-imidazo[1,2-b]pyridazin-2-yl]phenyl} cyclobutanamine UPLC-MS (Method 3):RT = 1.33 min; m/z (rel intensity) 424 (100 (M + H − 17)⁺), 441 (70,(M + H)⁺), 881 (20, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.54-1.66 (m,1H), 1.86-2.09 (m, 3H), 2.29-2.39 (m, 2H), 4.06 (s, 3H), 7.28 (s, 1H),7.41 (d, J = 8.5 Hz, 2H), 7.50-7.57 (m, 4H), 7.60 (d, J = 8.5 Hz, 2H),7.93 (s, 1H), 8.51 (t, J = 1.4 Hz, 1H), 9.29 (s, 1H). 25

  1-[4-(3-Phenylimidazo[1,2-b]pyridazin-2- yl)phenyl]cyclobutanamineUPLC-MS (Method 3): RT = 1.06 min; m/z (rel intensity) 324 (100 (M + H −17)⁺), 341 (40, (M + H)⁺); ES-m/z (rel intensity) 339 (100, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.55-1.67 (m, 1H), 1.86-2.09 (m, 3H),2.29-2.39 (m, 2H), 4.06 (s, 3H), 7.25 (dd, J = 9.2, 4.3 Hz, 1H), 7.37(d, J = 8.5 Hz, 2H), 7.43-7.52 (m, 5H), 7.57 (d, J = 8.5 Hz, 2H), 8.16(dd, J = 9.2, 1.5 Hz, 1H), 8.43 (dd, J = 4.5, 1.7 Hz, 1H). 26

  2-[4-(1-Aminocyclobutyl)phenyl]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6- carboxamide UPLC-MS (Method3): RT = 1.15 min; m/z (rel intensity) 411 (80 (M + H − 17)⁺), 427 (60,(M + H)⁺), 853 (70, (2M + H)⁺); ES-m/z (rel intensity) 425 (40, (M −H)⁻). 1H-NMR (DMSO-d₆): δ [ppm] 1.55-1.65 (m, 1H), 1.89-2.10 (m, 5H),2.28-2.37 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 4.34 (s, 3H), 7.13 (s, 1H),7.37 (d, J = 8.3 Hz, 2H), 7.46-7.53 (m, 5H), 7.58 (dm, J = 8.3 Hz, 2H),8.10 (q, J = 4.8 Hz, 1H). 27

  1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.25 min;m/z (rel intensity) 390 (100 (M + H − 17)⁺), 407 (80, (M + H)⁺), 813(10, (2M + H)⁺); ES-m/z (rel intensity) 405 (100, (M − H)⁻), 811 (10,(2M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm] 1.54-1.67 (m, 1H), 1.87-2.17 (m,5H), 2.29-2.38 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.46- 7.57 (m, 5H),7.64 (d, J = 8.1 Hz, 2H), 7.70-7.75 (m, 2H), 7.93, br s, 1H), 8.46 (d, J= 4.7 Hz,1H). 28

  2-[4-(1-Aminocyclobutyl)phenyl]-8-(2-methoxy-ethoxy)-3-phenylimidazo[1,2-b]pyridazine-6- carboxamide UPLC-MS (Method3): RT = 1.07 min; m/z (rel intensity) 441 (90 (M + H − 17)⁺), 458 (100,(M + H)⁺), 915 (30, (2M + H)⁺); ES-m/z (rel intensity) 456 (100, (M −H)⁻), 913 (10, (2M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm] 1.56-1.68 (m, 1H),1.88-2.10 (m, 4H), 2.29-2.39 (m, 3H), 3.34 (s, 3H), 3.77-3.82 (m, 2H),4.51-4.56 (m, 2H), 7.16 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.43- 7.61(m, 9H), 7.82 (br s, 1H). 29

  1-{4-[8-(Benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.52 min;m/z (rel intensity) 464 (100 (M + H − 17)⁺), 481 (80, (M + H)⁺), 961(50, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.55-1.66 (m, 1H), 1.89-1.98(m, 1H), 2.00-2.08 (m, 2H), 2.28-2.36 (m, 2H), 5.48 (s, 2H), 7.08 (s,1H), 7.34 (d, J = 8.6 Hz, 2H), 7.40-7.56 (m, 13H). 30

  1-[4-(6-Chloro-8-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT = 1.39 min;m/z (rel intensity) 402 (100 (M + H − 17)⁺), 419 (80, (M + H)⁺), 837(10, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.46 (t, J = 7.0 Hz, 3H),1.54- 1.65 (m, 1H), 1.87-2.07 (m, 5H), 2.27-2.36 (m, 2H), 4.43 (q, J =7.2 Hz, 2H), 6.93 (s, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.44- 7.54 (m, 7H).31

  Methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate UPLC-MS (Method 3): RT =1.22 min; m/z (rel intensity) 382 (80 (M + H − 17)⁺), 399 (100, (M +H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.55-1.68 (m, 1H), 1.86-2.10 (m, 3H),2.29-2.40 (m, 2H), 3.98 (s, 3H), 7.39 (d, J = 8.7 Hz, 2H), 7.48-7.53 (m,5H), 7.57 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 4.5 Hz, 1H), 8.58 (d, J =4.5 Hz, 1H). 32

  2-[4-(1-Aminocyclobutyl)phenyl]-3- phenylimidazo[1,2-b]pyridazin-8-olUPLC-MS (Method 3): RT = 0.69 min; m/z (rel intensity) 340 (70 (M + H −17)⁺), 357 (100, (M + H)⁺), 713 (20, (M + H)⁺); ES-m/z (rel intensity)355 (80, (M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm] 1.67-1.81 (m, 1H),2.03-2.19 (m, 1H), peak obscured by solvent signal, 5.84 (d, J = 5.8 Hz,1H), 7.32 (d, J = 8.5 Hz, 2H), 7.35-7.50 (m, 7H), 7.74 (d, J = 5.8 Hz,1H). 33

  1-{4-[6-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.05 min;m/z (rel intensity) 418 (40 (M + H − 17)⁺), 435 (20, (M + H)⁺); ES-m/z(rel intensity) 479 (80, (M − H + HCO₂H)⁻). 1H-NMR (DMSO-d₆): δ [ppm]1.55-1.69 (m, 1H), 1.86-2.12 (m, 3H), 2-31-2.41 (m, 2H), 5.84 (d, J =5.8 Hz, 1H), 7.34 (t, J = 8.9 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H),7.45-7.63 (m, 7H), 7.85 (d, J = 9.4 Hz, 1H), 8.01 (dd, J = 8.9, 5.5 Hz,2H), 8.25 (d, 9.4 Hz, 1H). 34

  2-[4-(1-Aminocyclobutyl)phenyl]-3- phenylimidazo[1,2-b]pyridazine-6,8-dicarboxamide (Approach 2) UPLC-MS (Method 3): RT = 1.03 min; m/z (relintensity) 410 (90 (M + H − 17)⁺), 427 (100, (M + H)⁺); ES-m/z (relintensity) 425 (30, (M − H)⁻), 851 (10, (2M − H)⁻). 1H-NMR (DMSO-d₆): δ[ppm] 1.56-1.72 (m, 1H), 1.92-2.04 (m, 1H), 2.07-2.18 (m, 2H), 2.33-2.42(m, 2H partially obscured by solvent signal), 7.44 (d, J = 8.5 Hz, 2H),7.48- 7.57 (m, 3H), 7.59-7.67 (m, 5H), 7.96 (br s, 1H), 8.20 (d, J = 2.6Hz, 2H), 8.47 (br s, 1H), 9.17 (br s, 1H). 35

  2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-amine UPLC-MS (Method 3): RT = 1.05 min;m/z (rel intensity) 339 (70 (M + H − 17)⁺), 356 (100, (M + H)⁺); ES-m/z(rel intensity) 337 (30, (M − H − 17)⁻), 851 (10, (2M − H)⁻). 1H-NMR(DMSO-d₆): δ [ppm] 1.55-1.66 (m, 1H), 1.90-1.99 (m, 1H), 2.03-2.11 (m,2H), 2.30-2.48 (m, 2H), 6.27 (s, 2H), 6.64 (d, J = 9.6 Hz, 1H), 7.30 (d,J = 8.6 Hz, 2H), 7.38-7.48 (m, 7H), 7.75 (d, J = 9.6 Hz, 1H), 8.27 (brs, 0.5H). 36

  1-{4-[6-(Methylsulfanyl)-3-phenylimidazo[1,2-b] pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.39 min; m/z (relintensity) 370 (100 (M + H − 17)⁺), 387 (80, (M + H)⁺). 1H-NMR(DMSO-d₆): δ [ppm] 1.53-1.66 (m, 1H), 1.86-2.09 (m, 5H), 2.28-2.38 (m,2H), 2.42 (s, 3H), 7.18 (d, J = 9.4 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H),7.42-7.59 (m, 7H), 7.98 (d, J = 9.4 Hz, 1H). 37

  N-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}acetamide UPLC-MS (Method 3): RT =1.08 min; m/z (rel intensity) 381 (80 (M + H − 17)⁺), 398 (100, (M +H)⁺); ES-m/z (rel intensity) 396 (100, (M − H)⁻). 1H-NMR (DMSO-d₆): δ[ppm] 1.53-1.67 (m, 1H), 1.88-2.10 (m, 3H), 2.05 (s, 3H), 2.28-2.39 (m,2H), 7.34 (d, J = 8.5 Hz, 2H), 7.42-7.54 (m, 7H), 7.92 (br d, J = 9.8Hz, 1H), 8.12 (d, J = 9.8 Hz, 1H), 10.69 (br s, 1H). 38

  N-{2-[4-(1-1-{4-[6-(Methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} cyclobutanamine UPLC-MS(Method 3): RT = 1.13 min; m/z (rel intensity) 402 (100 (M + H − 17)⁺),419 (60, (M + H)⁺), 837 (10, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm]1.65-1.80 (m, 1H), 1.98-2.13 (m, 1H), 2.28-2.39 (m, 2H), 3.35 (s, 3H),7.16 (br s, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.51- 7.62 (m, 5H), 7.68 (d,J = 8.5 Hz, 2H), 7.77 (d, J = 9.4 Hz, 1H), 8.50 (d, J = 9.4 Hz, 1H). 39

  Methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate UPLC-MS (Method 3): RT =1.22 min; m/z (rel intensity) 382 (100 (M + H − 17)⁺), 399 (50, (M +H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.60-1.75 (m, 1H), 1.93-2.08 (m, 1H),2.15-2.26 (m, 2H), peak obscured by solvent signal, 3.86 (s, 3H), 7.42(d, J = 8.5 Hz, 2H), 7.50-7.56 (m, 5H), 7.62 (d, J = 8.5 Hz, 2H), 7.75(d, J = 9.4 Hz, 1H), 8.31 (d, J = 9.4 Hz, 1H). 40

  N-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}-2,2,2- trifluoroacetamide UPLC-MS(Method 3): RT = 0.70 min; m/z (rel intensity) 435 (100 (M + H − 17)⁺),452 (70, (M + H)⁺); ES-m/z (rel intensity) 450 (100, (M − H)⁻). 1H-NMR(CD₃OD): δ [ppm] 1.82-1.90 (m, 1H), 2.11-2.19 (m, 1H), 2.64-2.70 (m,2H), 6.80 (d, J = 9.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.43-7.48 (m,3H), 7.52 (dm, J = 7.5 Hz, 2H), 7.58 (d, J = 8.3 Hz, 1H), 7.72 (d, J =9.8 Hz, 1H). 41

  1-[4-(6-Bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT = 1.33 min;m/z (rel intensity) 402 (100 (M + H − 17)⁺), 419 (80, (M + H)⁺). 1H-NMR(DMSO-d₆): δ [ppm] 1.62-1.69 (m, 1H), 1.95-2.02 (m, 1H), 2.06-2.11 (m,2H), 2.35-2.41 (m, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 9.4 Hz,1H), 7.52-7.60 (m, 7H), 8.19 (d, J = 9.4 Hz, 1H). 42

  1-{4-[6,8-Bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.74min; m/z (rel intensity) 512 (100 (M + H − 17)⁺), 529 (90, (M + H)⁺).1H-NMR (DMSO-d₆): δ [ppm] 1.62-1.69 (m, 1H), 1.95-2.02 (m, 1H),2.06-2.11 (m, 2H), 2.37-2.42 (m, 2H), 7.40 (t, J = 8.7 Hz, 2H), 7.45 (d,J = 8.3 Hz, 2H), 7.49-7.55 (m, 3H), 7.59 (t, J = 7.53 Hz, 2H), 7.64 (d,J = 8.3 Hz, 2H), 7.69 (2, J = 7.2 Hz, 2H), 8.12 (s, 1H), 8.18 (dd, J =9.0, 5.7 Hz, 2H), 8.69 (dd, J = 9.0, 5.7 Hz, 2H). 43

  1-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}ethanone UPLC-MS (Method 3): RT =1.28 min; m/z (rel intensity) 366 (100 (M + H − 17)⁺), 383 (90, (M +H)⁺), 765 (5, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.62-1.70 (m, 1H),1.96-2.04 (m, 1H), 2.07-2.12 (m, 2H), 2.37-2.43 (m, 2H), 2.56 (s, 3H),7.46 (d, J = 8.7 Hz, 2H), 7.52- 7.55 (m, 1H), 7.57-7.60 (m, 2H),7.65-7.69 (m, 4H), 7.74 (d, J = 9.4 Hz, 1H), 7.82 (d, J = 9.4 Hz, 1H).44

  1-{4-[8-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine UPLC-MS (Method 3): RT = 1.53 min;m/z (rel intensity) 418 (100 (M + H − 17)⁺), 435 (80, (M + H)⁺). 45

  N-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl} methanesulfonamide UPLC-MS (Method3): RT = 0.69 min; m/z (rel intensity) 417 (100 (M + H − 17)⁺), 434 (80,(M + H)⁺); ES-m/z (rel intensity) 432 (100, (M − H)⁻). 1H-NMR (DMSO-d₆):δ [ppm] 1.64-1.81 (m, 1H), 1.99-2.12 (m, 1H), 2.29-2.41 (m, 2H), peakobscured by solvent signal, 6.60 (d, J = 9.6 Hz, 1H), 7.33-7.44 (m, 5H),7.53-7.61 (m, 4H), 7.65-7.69 (m, 4H), 7.67 (d, J = 9.6 Hz, 1H). 46

  1-[4-(6-Chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT =1.53 min; m/z (rel intensity) 398 (100 (M + H − 17)⁺). 1H-NMR (DMSO-d₆):δ [ppm] 1.23-1.30 (m, 2H), 1.34-1.41 (m, 2H), 1.59-1.70 (m, 1H),1.92-2.03 (m, 1H), 2.09-2.20 (m, 2H), 2.33-2.39 (m, 1.6H, partiallyobscured by solvent signal), 2.56-2.64 (m, 1.9H, partially obscured bysolvent signal), 7.01 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.44-7.53 (m,5H), 7.56 (d, J = 8.3 Hz, 2H). 47

  1-[4-(3-Phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine UPLC-MS (Method 3): RT = 1.44 min;m/z (rel intensity) 366 (80 (M + H − 17)⁺), 383 (100 (M + H − 17)⁺).1H-NMR (DMSO-d₆): δ [ppm] 0.98 (t, J = 7.4 Hz, 3H), 1.52- 1.66 (m, 1H),1.84 (apparent sext, J = 7.6 Hz, 2H), 1.90-2.09 (m, 5H), 2.28-2.38 (m,2H), 2.99 (q, J = 7.5 Hz, 2H), 7.08 (d, J = 4.7 Hz, 1H), 7.37 (d, J =8.5 Hz, 2H), 7.43-7.57 (m, 8H). 48

  2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-amine UPLC-MS (Method 3): RT = 1.13 min;m/z (rel intensity) 339 (70 (M + H − 17)⁺), 356 (100 (M + H − 17)⁺);ES-m/z (rel intensity) 354 (20, (M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm]1.54-1.65 (m, 1H), 1.88-2.07 (m, 3H), 2.28-2.38 (m, 2H), 6.13 (d, J =5.5 Hz, 1H), 6.92 (br s, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.39-7.49 (m,5H), 7.52 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 5.5 Hz, 1H). 49

  N-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}acetamide UPLC-MS (Method 3): RT =1.23 min; m/z (rel intensity) 381 (100 (M + H − 17)⁺), 398 (100 (M + H −17)⁺); ES-m/z (rel intensity) 396 (100, (M − H)⁻). 1H-NMR (DMSO-d₆): δ[ppm] 1.53-1.66 (m, 1H), 1.88-2.15 (m, 5H), 2.28-2.38 (m, 2H), 2.30 (s,3H), 7.38 (d, J = 8.5 Hz, 2H), 7.43-7.52 (m, 5H), 7.59 (d, J = 8.3 Hz,2H), 7.90 (d, J = 5.5 Hz, 1H), 8.29 (d, J = 5.3 Hz, 1H).

Example 501-[4-(6-Chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a mixture of the tert-butyl{1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-32 (179 mg, 0.360 mmol, 1.0 eq) in DCM (2.29mL) and MeOH (1.44 mL) was added a solution of 4M hydrogen chloride indioxane (1.78 mL, 7.12 mmol, 20.0 eq) and the mixture was stirredovernight at rt. The mixture was poured onto ice, made alkaline withaqueous sodium hydroxide (2N) and extracted with DCM. The combinedorganic phases were washed with brine, dried and concentrated in vacuo.The crude mixture was purified via MPLC (Biotage Isolera; 10 g SNAPcartridge: DCM->DCM/ethanol 95/5) to give 64 mg (44% yield) of the titlecompound.

UPLC-MS (Method 2): RT=1.48 min; m/z=403 (M+H)⁺.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.59 (m, 1H), 1.93 (m, 1H), 2.02 (m,2H), 2.11 (br s, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 2.64 (s, 3H), 7.37 (d,2H), 7.46-7.52 (m, 5H), 7.54 (d, 2H).

Example 51 Methyl2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate

A mixture of crude tert-butyl(1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that wasprepared in a manner analgous to that described for Intermediate ExampleInt-1-A](630 mg, ˜90% purity, 1.28 mmol, 1.0 eq), methyl6-amino-4,5-dimethylpyridazine-3-carboxylate [that was prepared in amanner analgous to that described for Intermediate Example Int-34](257mg, 1.28 mmol, 1.0 eq), N,N-diisopropylethylamine (220 μL, 1.28 mmol,1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. Oncooling the mixture was partitioned between DCM and water, stirredvigorously and filtered through a silicone coated filter paper. Thefiltrate was concentrated in vacuo. The crude mixture was purified viapreparative reversed phase HPLC to give 89 mg (16% yield) of the titlecompound directly as the free amine.

UPLC-MS (Method 2): RT=1.35 min; m/z=427 (M+H)⁺.

1H-NMR (400 MHz, MeOD): δ [ppm]=1.75 (m, 1H), 2.06 (m, 1H), 2.24 (m,2H), 2.44 (s, 3H), 2.56 (m, 2H), 2.71 (s, 3H), 3.93 (s, 3H), 7.38-7.47(m, 5H), 7.48-7.54 (m, 2H), 7.60 (d, 2H).

Example 522-[4-(1-Aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide

A solution of methyl2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate[that was prepared in a manner analgous to that described for Example51](80 mg, ˜90% purity, 0.170 mmol, 1.0 eq) in 2.41 ml 7N ammonia inMeOH (˜100 eq of NH3) was heated for 2 hours at 130° C. by the use of asingle mode microwave oven (Biotage). On cooling the volatile componentswere removed in vacuo. The crude mixture was purified via MPLC (BiotageIsolera; 11 g SNAP NH2 cartridge: hexane/EtOAc 1:1->EtOAc) to give 54 mg(77% yield) of the title compound.

UPLC-MS (Method 2): RT=1.22 min; m/z=412 (M+H)⁺.

1H-NMR (400 MHz, MeOD): δ [ppm]=1.74 (m, 1H), 2.06 (m, 1H), 2.24 (m,2H), 2.48 (s, 3H), 2.55 (m, 2H), 2.70 (s, 3H), 7.38-7.48 (m, 5H),7.52-7.57 (m, 2H), 7.60 (d, 2H).

Example 531-[4-(6-Methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a solution of methyl tert-butyl{1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate[that was prepared in a manner analgous to that described forIntermediate Example Int-34](80 mg, ˜80% purity, 0.160 mmol, 1.0 eq) inDCM (1.03 mL) and MeOH (0.65 mL) was added a solution of 4M hydrogenchloride in dioxane (0.80 mL, 3.21 mmol, 20.0 eq) and the mixture wasstirred for overnight at rt. The mixture was poured onto ice, madealkaline with aqueous sodium hydroxide (2N) and extracted with DCM. Thecombined organic phases were washed with brine, dried and concentratedin vacuo. The crude mixture was purified via preparative HPLC to give 44mg (62% yield) of the title compound.

UPLC-MS (Method 2): RT=1.48 min; m/z=399 (M+H)⁺.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.61 (m, 1H), 1.94 (m, 1H), 2.05 (m,2H), 2.16 (s, 3H), 2.34 (m, 2H), 2.52 (s, 3H), 3.81 (s, 3H), 7.32-7.42(m, 3H), 7.45 (m, 2H), 7.51 (m, 2H), 7.55 (m, 2H), NH2 not assigned.

Example 541-{4-[7,8-Dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutanamine

To a mixture of the tert-butyl(1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-35 (95 mg, 0.190 mmol, 1.0 eq) in DCM (1.19 mL)and MeOH (0.75 mL) was added a solution of 4M hydrogen chloride indioxane (0.92 mL, 3.69 mmol, 20.0 eq) and the mixture was stirredovernight at rt. The mixture was poured onto ice, made alkaline, treatedwith DCM and filtered through a phase separator. The volatile componentsof the organic phase were removed in vacuo to give 75 mg (94% yield) ofthe title compound.

UPLC-MS (Method 2): RT=1.55 min; m/z=415 (M+H)⁺.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.60 (m, 1H), 1.87-2.09 (m, 3H), 2.12(br s, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 2.38 (s, 3H), 2.55 (s, 3H),7.33-7.50 (m, 5H), 7.51-7.60 (m, 4H).

Example 551-[4-(6-Ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

To a mixture of the tert-butyl{1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-36 (210 mg, 0.410 mmol, 1.0 eq) in DCM (2.64mL) and MeOH (1.66 mL) was added a solution of 4M hydrogen chloride indioxane (2.05 mL, 8.19 mmol, 20.0 eq) and the mixture was stirredovernight at rt. The mixture was poured onto ice, made alkaline, treatedwith DCM and filtered through a phase separator. The volatile componentsof the organic phase were removed in vacuo to give 145 mg (82% yield) ofthe title compound.

UPLC-MS (Method 2): RT=1.56 min; m/z=414 (M+H)⁺.

1H-NMR (400 MHz, d6-DMSO): δ [ppm]=1.30 (t, 3H), 1.59 (m, 1H), 1.87-2.10(m, 5H), 2.15 (s, 3H), 2.33 (m, 2H), 2.51 (s, 3H), 4.17 (q, 2H), 7.34(m, 2H), 7.37-7.50 (m, 4H), 7.50-7.56 (m, 3H).

Example 56 Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)-imidazo[1,2-b]pyridazine-6-carboxylate

A solution of1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanaminethat was prepared in a manner analgous to that described for Example 19(0.59 g, 1.34 mmol) in MeOH (2.2 mL) and THF (0.2 mL) in an autoclavewas added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride(0.22 g, 0.27 mmol, 0.20 equiv) and triethylamine (0.20 mL, 1.47 mmol,1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar)three times, then was pressurized with CO (5.2 bar), stirred at roomtemperature 30 min., and briefly placed under reduced atmosphere (0.06bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.),heated to 110° C., and stirred at this temperature for 22 h.

The resulting solution was concentrated under reduced pressure. Theresulting material was purified using MPLC (Biotage Isolera; SNAP 25 gcartridge: 100% DCM 2.0 min., gradient to 95% DCM/5% MeOH 1.0 min., 95%DCM/5% MeOH 2.5 min., gradient to 90% DCM/10% MeOH 1.5 min., 90% DCM/10%MeOH 4.5 min.) to give an impure material (0.45 g). A portion of thematerial was further purified using preparative HPLC (Agilent Prep 1200equipped with 2× Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigdeC18 5 μm 100×30 mm column; gradient from 70% water with 0.2% NH₃/30%CH₃CN to 40% water with 0.2% NH₃/60% CH₃CN over 17.5 min, gradient from40% water with 0.2% NH₃/60% CH₃CN to 100% CH₃CN over 2.5 min) to givemethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate(0.013 g, 17% based on purification of 11%):

UPLC-MS (Method 3): RT=1.28 min; m/z (rel intensity) 448 (100(M+H-17)+), 465 (80, (M+H)⁺); ES− m/z (rel intensity) 463 (40, (M−H)⁻).

1H-NMR (d6-DMSO): δ 1.56-1.67 (m, 1H), 1.91-2.00 (m, 1H), 2.02-2.11 (m,2H), 2.32-2.39 (m, 2H), 3.88 (s, 3H), 7.42 (d, J=8.6 Hz, 2H), 7.51-7.58(m, 5H), 7.65 (d, J=8.3 Hz, 2H), 7.77 (d, J=2.3 Hz, 1H), 7.98 (br s,1H), 8.28 (s, 1H).

The following examples were prepared in a manner analogous to Example 56by reacting the corresponding halide with MeOH and CO in the presence of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride

Example Structure/Name Characterization 57

UPLC-MS (Method 3): RT = 1.29 min; m/z (rel intensity) 426 (100 (M + H −17)⁺), 443 (100, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.48 (t, J = 7.1Hz, 3H), 1.56- 1.65 (m, 1H), 1.89-2.14 (m, 5H), 2.29-2.36 (m, 2H), 3.85(s, 3H), 4.47 (q, J = 7.1 Hz, 2H), 7.14 (s, 1H), 7.37 (d, J = 8.6 Hz,2H), 7.47-7.54 (m, 7H). Methyl 2-[4-(1- aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2- b]pyridazine-6-carboxylate 58

UPLC-MS (Method 3): RT = 1.25 min; m/z (rel intensity) 448 (100 (M + H −17)⁺), 465 (80, (M + H)⁺), 929 (20, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ[ppm] 1.57-1.68 (m, 1H), 12.90-2.00 (m, 1H), 2.02-2.12 (m, 2H),2.31-2.39 (m, 2H), 3.90 (s, 3H), 7.27 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H),7.52-7.59 (m, 6H), 7.63 (d, J = 8.5 Hz, 2H), 8.09 (s, 1H), 8.57 (s, 1H),9.31 (s, 1H). Methyl 2-[4-(1- aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3- phenylimidazo[1,2- b]pyridazine-6-carboxylate

Example 59 tert-Butyl{1-[4-(8-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate

A solution of methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylatethat was prepared in a manner analgous to that described for Example 31(0.040 g, 0.10 mmol) in a solution of ammonia in MeOH (7N, 0.7 mL, 5.0mmol, 50 equiv) was irradiated in a microwave apparatus at 130° C. for90 min. The resulting mixture was concentrated under reduced pressure.The resulting material was triturated with diisopropyl ether to givetert-butyl{1-[4-(8-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.025 g, 60%):

UPLC-MS (Method 3): RT=1.17 min; m/z (rel intensity) 367 (100,(M+H-17)+), 384 (70, (M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.54-1.69 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.13(m, 2H), 2.31-2.40 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.48-7.56 (m, 5H),7.61 (d, J=8.5 Hz, 2H), 7.75 (d, J=4.7 Hz, 1H), 8.41 (br s, 1H), 8.63(d, J=4.7 Hz, 1H), 9.25 (br s, 1H).

The following examples were prepared in a manner analogous to Example 59by reacting the corresponding ester with ammonia

Example Structure/Name Characterization 60

UPLC-MS (Method 3): RT = 1.11 min; m/z (rel intensity) 433 (100 (M + H −17)⁺), 450 (80, (M + H)⁺), 921 (10, (2M + Na)⁺); ES− m/z (rel intensity)448 (100, (M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm] 1.56-1.68 (m, 1H),1.89-2.10 (m, 3H), 2.31-2.41 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.47-7.56 (m, 4H), 7.62-7.68 (m, 4H), 7.75 (d, J = 2.0 Hz, 1H), 7.85 (br s,1H), 7.95 (br s, 1H), 8.25 (s, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3- yl)imidazo[1,2-b]pyridazine-6- carboxamide 61

UPLC-MS (Method 3): RT = 1.11 min; m/z (rel intensity) 411 (60 (M + H −17)⁺), 428 (70, (M + H)⁺); ES− m/z (rel intensity) 446 (10, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.47 (t, J = 7.1 Hz, 3H), 1.57- 1.65 (m, 1H),1.89-2.14 (m, 5H), 2.28-2.37 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 7.12 (s,1H), 7.37 (d, J = 8.3 Hz, 2H), 7.43- 7.55 (m, 2H), 7.62-7.68 (m, 6H),7.59 (d, J = 8.1 Hz, 2H), 7.82 (br s, 1H). 2-[4-(1-Aminocyclobutyl)phenyl]-8- ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide

The following examples were prepared in a manner analogous to Example 59by reacting the corresponding ester with methylamine

Example Structure/Name Characterization 62

1H-NMR (CD₃OD): δ [ppm] 1.70-1.82 (m, 1H), 1.99-2.14 (m, 1H), 2.19-2.31(m, 2H), 2.50-2.61 (m, 2H), 7.29 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H),7.52- 7.61 (m, 5H), 7.68 (d, J = 8.5 Hz, 2H), 7.99 (s, 1H), 8.33 (s,1H), 9.38 (s, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-N-methyl-3- phenylimidazo[1,2-b]pyridazine-6-carboxamide 63

UPLC-MS (Method 3): RT = 1.25 min; m/z (rel intensity) 381 (100 (M + H −17)⁺), 398 (50, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.60-1.70 (m, 1H),1.93-2.03 (m, 1H), 2.07-2.14 (m, 2H), 2.35-2.43 (m, 2H), 3.05 (d, J =4.8 Hz, 3H), 7.44 (d, J = 8.5 Hz, 2H), 7.51-7.57 (m, 5H), 7.68 (d, J =8.5 Hz, 2H), 7.79 (d, J = 4.5 Hz, 1H), 8.66 (d, J = 4.5 Hz, 1H), 9.75(q, J = 4.5 Hz, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2- b]pyridazine-8-carboxamide 64

UPLC-MS (Method 3): RT = 1.27 min; m/z (rel intensity) 451 (70 (M + H −17)⁺), 468 (100, (M + H)⁺), 935 (70, (2M + H)⁺); ES− m/z (rel intensity)466 (100, (M − H)⁻), 933 (10, (2M − H)⁻), 1H-NMR (DMSO-d₆): δ [ppm]0.41-0.46 (m, 2H), 0.62-0.68 (m, 2H), 1.33-1.41 (m, 1H), 1.55-1.65 (m,1H), 1.90-2.10 (m, 5H), 2.29-2.37 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H),4.24 (d, J = 7.3 Hz, 2H), 7.08 (s, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.45-7.53 (m, 5H), 7.58 (d, J = 6.8 Hz, 2H), 8.08 (q, J = 4.6 Hz, 1H). 65

UPLC-MS (Method 3): RT = 1.18 min; m/z (rel intensity) 447 (100 (M + H −17)⁺), 464 (90, (M + H)⁺), 927 (5, (2M + H)⁺); ES− m/z (rel intensity)462 (40, (M- H)⁻), 925 (10, (2M − H)⁻), 1H-NMR (DMSO-d₆): δ [ppm]1.56-1.66 (m, 1H), 1.90-1.99 (m, 1H), 2.00-2.09 (m, 2H), 2.31-2.39 (m,2H), 2.80 (d, J = 4.8 Hz, 3H), 7.42 (d, J = 8.3 Hz, 2H), 7.48-7.55 (m,3H),7.61-7.65 (m, 4H), 7.75 (d, J = 2.3 Hz, 1H), 7.95 (br d, J = 1.8 Hz,1H), 8.15 (br q, J = 4.8 Hz, 1H), 8.24 (s, 1H).

The following examples were prepared in a manner analogous to Example 59by reacting the corresponding ester with ethylamine

Example Structure/Name Characterization 66

UPLC-MS (Method 3): RT = 1.17 min; m/z (rel intensity) 395 (100 (M + H −17)⁺), 412 (50, (M + H)⁺). 1H-NMR (DMSO-d₆): δ [ppm] 1.07 (t, J = 7.1Hz, 3H), 1.72- 1.84 (m, 1H), peak obscured by solvent signal, 2.05-2.16(m, 1H), 2.54-2.65 (m, 2H), 2.31- 3.27 (q, J = 7.3 HZ, 2H), 7.46- 7.55(m, 5H),7.61 (dd; J = 7.6, 1.5 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.73(d, J = 9.4 Hz, 1H), 8.30 (d, J = 9.4 Hz, 1H), 8.15 (br q, J = 4.8 Hz,1H), 8.24 (s, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-N-ethyl-3-phenylimidazo[1,2- b]pyridazine-6-carboxamide

Example 672-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]-pyridazine-6-carboxylicacid

To a solution of methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylatethat was prepared in a manner analgous to that described for Example 56(0.19 g, 0.41 mmol) in MeOH (5 mL) was added an aqueous NaOH solution(10% 0.65 mL, 1.64 mmol, 4.0 equiv). The resulting mixture was stirredat room temperature for 48 h. Water 10 mL) was added to the resultingmixture and the pH was adjusted to pH 4 using an aqueous 2N HClsolution. The resulting precipate was collected by filtration, andrecrystallized from dimethyl sulfoxide to give2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylicacid (0.012 g, 6%).

UPLC-MS (Method 3): RT=0.70 min; m/z (rel intensity) 434 (40 (M+H-17)+),451 (100, (M+H)⁺); ES− m/z (rel intensity) 449 (70, (M−H)⁻), 899 (50,(2M−H)⁻),

1H-NMR (DMSO-d₆): δ [ppm]1.70-1.83 (m, 1H), 2.04-2.17 (m, 1H), 2.03-2.13(m, 2H), 2.53-2.64 (m, 3.5H partially obscured by solvent signal), 7.50(d, J=8.5 Hz, 2H), 7.52-7.58 (m, 5H), 7.75-7.80 (m, 3H), 7.97 (d, J=2.3Hz, 1H), 8.30 (s, 1H).

Example 682-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide

To a solution of2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylicacid that was prepared in a manner analgous to that described forExample 8 (0.15 g, 0.39 mmol) and methylamine (2M in THF, 1.43 mL, 2.93mmol, 7.5 equiv) in DMF (1 mL) was added PYBOP (0.22 g, 0.43 mmol 1.10equiv) and N,N-diisopropylethylamine (0.27 mL, 1.56 mmol, 4.0 equiv).The resulting mixture was stirred at room temperature for 25 h, then wastreated with water (10 mL). The resulting aqueous mixture was extractedwith EtOAc (4×15 mL). The combined organic phases were washed with water(2×15 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure.The resulting material was triturated with MeOH to give2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide(0.085 g, 55%):

UPLC-MS (Method 3): RT=1.09 min; m/z (rel intensity) 381 (100(M+H-17)+), 398 (70, (M+H)⁺), 795 (10, (2M+H)⁺); ES− m/z (rel intensity)396 (40, (M−H)⁻).

1H-NMR (DMSO-d₆): δ [ppm]1.55-1.66 (m, 1H), 1.89-2.08 (m, 5H), 2.28-2.38(m, 2H), 2.78 (d, J=4.7 Hz, 3H), 7.38 (d, J=8.3 Hz, 2H), 7.46-7.56 (m,5H), 7.61 (dd, J=7.7, 1.3 Hz, 2H), 7.68 (d, J=9.4 Hz, 1H), 8.16 (br q,J=4.7 Hz, 1H), 8.26 (s, 1H).

The following examples were prepared in a manner analogous to Example 68by the PYBOP-mediated reaction of the appropriate carboxylic acid withthe appropriate amine

Example Structure/Name Characterization 69

UPLC-MS (Method 3): RT = 1.09 min; m/z (rel intensity) 395 (100 (M + H −17)⁺), 412 (90, (M + H)⁺), 823 (10, (2M + H)⁺); ES− m/z (rel intensity)426 (100, (M − H)⁻), 853 (10, (2M − H)⁻). 1H-NMR (DMSO-d₆): δ [ppm]1.56-1.65 (m, 1H), 1.89-2.07 (m, 5H), 2.28-2.36 (m, 2H), 2.97 (s, 3H),2.99 (s, 3H), 7.36- 7.39 (m, 3H), 7.45-7.54 (m, 5H),7.57 (d; J = 8.3 Hz,2H), 8.24 (d, J = 9.4 Hz, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenylimidazo[1,2- b]pyridazine-6-carboxamide 70

UPLC-MS (Method 3): RT = 0.99 min; m/z (rel intensity) 411 (100 (M + H −17)⁺), 427 (80, (M + H)⁺), 855 (10, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ[ppm] 1.58-1.66 (m, 1H), 1.90-2.08 (m, 5H), 2.29-2.37 (m, 2H), 3.33 (q,J = 5.8 Hz, 2H), 3.47 (q, J = 5.6 Hz, 2H), 4.75 (t, J = 5.3 Hz, 1H),7.39 (d, J = 8.3 Hz, 2H), 7.45-7.54 (m, 3H),7.56 (d; J = 8.3 Hz, 2H),7.61 (dm, J = 8.3 Hz, 2H), 7.70 (d, J = 9.4 Hz, 1H), 8.06 (t, J = 6.1Hz, 1H), 8.28 (d, J = 9.60 Hz, 1H). 2-[4-(1-Aminocyclobutyl)phenyl]-N-(2- hydroxyethyl)-3- phenylimidazo[1,2-b]pyridazine-6-carboxamide 71

UPLC-MS (Method 3): RT = 1.02 min; m/z (rel intensity) 477 (60 (M + H −17)⁺), 494 (100, (M + H)⁺); ES− m/z (rel intensity) 492 (20, (M − H)⁻).1H-NMR (DMSO-d₆): δ [ppm] 1.56-1.66 (m, 1H), 1.90-2.14 (m, 5H),2.32-2.39 (m, 2H), 3.36 (q, J = 5.8 Hz, 2H), 3.49 (q, J = 5.6 Hz, 2H),4.76 (t, J = 5.3 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.47-7.55 (m, 3H),7.62-7.67 (m, 4H),7.76 (d, J = 2.3 Hz, 1H), 7.94 (br s, 1H), 8.05 (br t,J = 5.6 Hz, 1H), 8.27 (s, 1H). 2-[4-(1- Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-(1H- pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide

Example 72 Methyl3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propanoateStep 1: Methyl(2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclo-butyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate

A solution of tert-butyl(1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6 (0.50 g, 0.84 mmol), methyl acrylate (0.11mL, 1.3 mmol, 1.5 equiv) and triethylamine (0.13 mL, 0.96 mmol, 1.1equiv) in acetonitrile (6 mL) was placed under an argvon atmosphere. Tothis was added tri(2-tolyl)phosphine (0.043 g, 0.14 mmol, 0.17 equiv)and palladium(II) acetate (0.013 g, 0.059 mmol, 0.07 equiv). Theresulting mixture was irradiated in a microwave apparatus at 150° C. for60 min. The resulting mixture was then added to water (15 mL). Theresulting mixture was extracted with EtOAc (2×25 mL). The combinedorganic phases were washed with water (25 mL), dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting material was purifiedusing MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min,gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min,gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min,gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give methyl(2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate(0.50 g, 99%) which was used without further purification.

Step 2: Methyl3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-yl}propanoate

To a mixture of methyl(2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylatethat was prepared in a manner analgous to that described for Example 72,Step 1 (0.50 g, 0.83 mmol) and 10% palladium on carbon (0.26 g) in amixture of ethanol (14 mL) and THF (5 mL) was placed under a hydrogenatmosphere at room temperature for 1 h. The resulting mixture wastreated with additional 10% palladium on carbon (0.26 g) and placedunder a hydrogen atmosphere for 1 h. Solids were removed by filtrationand washed with ethanol (20 mL). The combined organic solutions weretreated with 10% palladium on carbon (0.26 g) and placed under ahydrogen atmosphere for 1 h. Solids were removed by filtration andwashed with ethanol (20 mL). The combined organic solutions wereconcentrated under reduced pressure. The resulting material was purifiedusing MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min,gradient to 80% hexane/20% EtOAc 1.5 min, gradient to 74% hexane/26%EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.0 min, gradient to 50%hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 6.4 min, gradient to 25%hexane/75% EtOAc 3.5 min, 25% hexane/75% EtOAc 5.3 min gradient to 100%EtOAc 5.3 min, 100% EtOAc 21.2 min). The resulting material was furtherpurified using preparative HPLC (Agilent Prep 1200 equipped with 2× PrepPump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mmcolumn; gradient from 100% water with 0.1% HCO₂H to 70% water with 0.1%HCO₂H/30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO₂H/70%MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9min) to give methyl3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propanoate(0.003 g, 1%):

UPLC-MS (Method 3): RT=0.97 min; m/z (rel intensity) 410 (500(M+H-17)+), 427 (60, (M+H)⁺).

1H-NMR (CD₃OD): δ [ppm]1.76-1.89 (m, 1H), 2.04-2.18 (m, 1H), 2.30-2.41(m, 2H), 2.58-2.69 (m, 2H), 2.97 (t, J=7.4 Hz, 2H), 3.40 (t, J=7.5 Hz,2H), 3.68 (s, 3H), 7.10 (d, J=4.5 Hz, 1H), 7.41-7.47 (m, 5H), 7.48-7.53(m, 2H), 7.65 (d, J=8.5 Hz, 2H), 8.29 (d, J=4.7 Hz, 1H).

Example 731-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]-phenyl}cyclobutanamine

To a solution of1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanaminethat was prepared in a manner analgous to that described for Example 19(0.14 g, 0.32 mmol) and sodium methoxide (0.051 g, 0.95 mmol, 3.0 equiv)in MeOH (0.8 mL) was irradiated in a microwave apparatus at 120° C. for90 min. The resulting mixture was added to water 10 mL. The aqueousmixture was extracted with DCM (3×15 mL), dried (Na₂SO₄ anh.) andconcentrated under reduced pressure. The resulting material was purifiedusing MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min,gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min,gradient to 50% hexane/50% EtOAc 2.5 min, 50% hexane/50% EtOAc 3.5 min,gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give an oil whichwas triturated with MeOH to give1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine(0.052 g, 36%):

UPLC-MS (Method 3): RT=1.37 min; m/z (rel intensity) 420 (100(M+H-17)+), 437 (60, (M+H)⁺); ES− m/z (rel intensity) 435 (80, (M−H)⁻).

1H-NMR (DMSO-d₆): δ [ppm]1.55-1.66 (m, 1H), 1.87-2.13 (m, 5H), 2.29-2.39(m, 2H), 3.82 (s, 3H), 7.32 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.42-7.53(m, 3H), 7.56-7.62 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.91 (br s, 1H).

The following examples were prepared in a manner analogous to Example 73by the reaction of the sodium methoxide with the appropriate halide

Example Structure/Name Characterization 74

UPLC-MS (Method 3): RT = 1.38 min; m/z (rel intensity) 434 (100 (M + H −17)⁺), 451 (80, (M + H)⁺), 901 (20, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ[ppm] 1.51-1.65 (m, 1H), 1.85-2.15 (m, 5H), 2.27-2.37 (m, 2H), 3.84 (s,3H), 4.02 (s, 3H), 6.92 (d, J = 1.9 Hz, 1H), 7.06 (s, 1H), 7.35 (d, J =8.5 Hz, 2H), 7.43- 7.53 (m, 5H),7.57-7.62 (m, 3H).1-{4-[6-Methoxy-8-(1-methyl- 1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin- 2-yl]phenyl}cyclobutanamine 75

1H-NMR (DMSO-d₆): δ [ppm] 1.60-1.65 (m, 1H), 1.93-2.02 (m, 1H),2.05-2.14 (m, 4H), 2.35-2.41 (m, 2H), 3.90 (s, 3H), 7.43 (d, J = 8.5 Hz,2H), 7.46 (s, 1H), 7.48-7.59 (m, 5H),7.65 (dM, J = 7.3 Hz, 2H), 8.41 (d,J = 6.3 Hz, 2H), 8.83 (d, J = 6.3 HZ, 2H). 1-{4-[6-Methoxy-3-phenyl-8-(pyridin-4-yl)imidazo[1,2- b]pyridazin-2- yl]phenyl}cyclobutanamine

The following examples were prepared in a manner analogous to Example 73by the reaction of the sodium ethoxide with the appropriate halide

Example Structure/Name Characterization 76

UPLC-MS (Method 3): RT = 1.46 min; m/z (rel intensity) 412 (100 (M + H −17)⁺), 429 (90, (M + H)⁺), 857 (50, (2M + H)⁺). 1H-NMR (DMSO-d₆): δ[ppm] 1.27 (t, J = 7.1 Hz, 3H), 1.43 (t, J = 7.1 HZ, 3H), 1.56-1.64 (m,1H), 1.89-2.09 (m, 5H), 2.28- 2.36 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H),4.32 (q, J = 7.1 Hz, 2H), 6.36 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H),7.38-7.48 (m, 5H),7.52 (dm, J = 8.1 Hz, 2H). 1-[4-(6,8-Diethoxy-3-phenylimidazo[1,2-b]pyridazin- 2-yl)phenyl]cyclobutanamine

Example 771-[4-(8-Butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine

A mixture of ethyl{1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate(0.12 g, 0.24 mmol) and potassium hydroxide (powder, 0.077 g, 1.17 mmol,5.0 equiv) in n-butanol (2.5 mL) was heated at the reflux temperaturefor 24 h. The resulting mixture was cooled to room temperature andseparated between a 4:1 DCM/isopropanol solution (50 mL) and water 50mL). The organic phase was washed with a saturated aqueous NaCl solution(25 mL), dried (Na₂SO₄ anh.) and concentrated under reduced pressure.The resulting material was purified using MPLC (Biotage Isolera; SNAP 10g cartridge: 100% DCM 4.0 min., gradient to 95% DCM/5% MeOH 1 min., 95%DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10%MeOH 3.5 min., gradient to 80% DCM/20% MeOH 6 min., 80% DCM/20% MeOH 4.7min.) to give1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.013 g, 9%):

1H-NMR (DMSO-d₆): δ [ppm]0.97 (t, J=7.5 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H),1.49 (sext, J=7.5 Hz, 2H), 1.56-1.67 (m, 1H), 1.83 apparent (pent, J=7.0Hz, 2H), 1.91-2.24 (m, 5H), 2.31-2.39 (m, 2H), 4.17 (q, J=7.3 Hz, 2H),4.30 (t, J=6.6 Hz, 2H), 6.40 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.40-7.50(m, 5H), 7.53-7.56 (m, 2H).

Example 781-[4-(6-Ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutan-amine

A mixture of tert-butyl{1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-6.2 (0.050 g, 0.11 mmol) and potassiumhydroxide (powder, 0.050 g, 0.89 mmol, 8.5 equiv) in ethanol (0.8 mL)was irradiated in a microwave apparatus at 120° C. for 120 min. Theresulting mixture was added to ice water (10 mL). The aqueous mixturewas extracted with a 4:1 DCM/isopropanol solution (4×10 mL). Thecombined organic phases were dried (Na₂SO₄ anh.) and concentrated underreduced pressure. The resulting material was purified using MPLC(Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90%DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20%MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine(0.017 g, 42%):

UPLC-MS (Method 3): RT=1.39 min; m/z (rel intensity) 368 (100(M+H-17)+), 385 (80, (M+H)⁺), 769 (10, (2M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.28 (t, J=7.0 Hz, 3H), 1.53-1.65 (m, 1H),1.87-2.08 (m, 5H), 2.27-2.33 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 6.88 (d,J=9.6 Hz, 1H), 1H), 7.35 (d, J=8.5 Hz, 2H), 7.41-7.56 (m, 7H), 8.03 (d,J=9.6 Hz, 1H).

Example 792-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol

A mixture of tert-butyl(1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamatethat was prepared in a manner analgous to that described forIntermediate Example Int-5 (0.25 g, 0.53 mmol) in N-methylpyrrolidone (5mL) was warmed to 100° C., then sodium sulfide (0.21 g, 2.66 mmol, 5.0equiv) was added and the mixture was heated to 160° C. for 10 minutes.The resulting mixture was added to ice water (15 mL). The aqueousmixture was made acidic with an aqueous 2N HCl solution, then wasbuffered with a saturated aqueous sodium bicarbonate solution. Theresulting precipitate was removed by filtration, washed with water, anddried at 50° C. under vacuum to give2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol(0.10 g, 53%):

UPLC-MS (Method 3): RT=0.61 min; m/z (rel intensity) 340 (100(M+H-17)+), 357 (90, (M+H)⁺), 713 (20, (2M+H)⁺); ES− m/z (rel intensity)355 (100, (M−H)⁻), 711 (100, (2M−H)⁻).

1H-NMR (DMSO-d₆): δ [ppm]1.55-1.66 (m, 1H), 1.86-1.99 (m, 1H), 2.20-2.11(m, 2H), 2.30-2.38 (m, 2H), 6.70 (d, J=9.6 Hz, 1H), 7.32 (d, J=8.3 Hz,2H), 7.38-7.49 (m, 7H), 7.88 (d, J=9.6 Hz, 1H).

Example 80 Methyl({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate

To a solution of2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-olthat was prepared in a manner analgous to that described for Example 79(0.093 g, 0.26 mmol) in DMF (2.5 mL) was added cesium carbonate (0.26 g,0.79 mmol, 3.0 equiv) and bromoacetic acid methyl ester (0.03 mL, 0.31mmol, 1.20 equiv). The resulting mixture was stirred at room temperaturefor 1 h, then was warmed to 60° C. for 3 h. The resulting mixture wasdiluted with water (10 mL). The aqueous mixture was extracted with EtOAC(3×10 mL). The combined organic phases were dried (Na₂SO₄ anh.) andconcentrated under reduced pressure. The resulting material was furtherpurified using preparative HPLC (Agilent Prep 1200 equipped with 2× PrepPump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mmcolumn; gradient from 100% water with 0.1% HCO₂H to 70% water with 0.1%HCO₂H/30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO₂H/70%MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9min) to give methyl({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate(0.056 g, 49%):

UPLC-MS (Method 3): RT=1.21 min; m/z (rel intensity) 412 (100(M+H-17)+), 429 (60, (M+H)⁺), 857 (10, (2M+H)⁺).

1H-NMR (DMSO-d₆): δ [ppm]1.54-1.68 (m, 1H), 1.86-2.11 (m, 3H), 2.30-2.39(m, 2H), 3.56 (s, 3H), 4.81 (s, 2H), 7.03 (d, J=9.6 Hz, 1H), 7.37 (d,J=8.5 Hz, 2H), 7.41-7.47 (m, 5H), 7.52 (d, J=8.5 Hz, 2H), 8.12 (d, J=9.6Hz, 1H).

Biological Investigations

The following assays can be used to illustrate the commercial utility ofthe compounds according to the present invention.

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Biological Assay 1.0: Akt1 Kinase Assay

Akt1 inhibitory activity of compounds of the present invention wasquantified employing the Akt1 TR-FRET assay as described in thefollowing paragraphs.

His-tagged human recombinant kinase full-length Akt1 expressed in insectcells was purchased form Invitrogen (part number PV 3599). As substratefor the kinase reaction the biotinylated peptidebiotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which canbe purchased e.g. from the company Biosynthan GmbH (Berlin-Buch,Germany).

For the assay 50 nl of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution ofAkt1 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl₂, 1 mMdithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μl of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μl assay volume is 10 μM) and substrate (1.67 μM=>final conc. in the 5μl assay volume is 1 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofAkt1 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 0.05 ng/μl(final conc. in the 5 μl assay volume). The reaction was stopped by theaddition of 5 μl of a solution of HTRF detection reagents (200 nMstreptavidine-XL665 [Cisbio] and 1.5 nM anti-phosho-Serine antibody[Millipore, cat. #35-001] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouseIgG antibody [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA,0.1% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). Theresulting mixture was incubated 1 h at 22° C. to allow the binding ofthe biotinylated phosphorylated peptide to the streptavidine-XL665 andthe antibodies. Subsequently the amount of phosphorylated substrate wasevaluated by measurement of the resonance energy transfer from theanti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit using an in-house software.

Biological Assay 2.0: Akt2 Kinase Assay

Akt2 inhibitory activity of compounds of the present invention wasquantified employing the Akt2 TR-FRET assay as described in thefollowing paragraphs.

His-tagged human recombinant kinase full-length Akt2 expressed in insectcells and activated by PDK1 was purchased form Invitrogen (part numberPV 3975). As substrate for the kinase reaction the biotinylated peptidebiotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which canbe purchased e.g. from the company Biosynthan GmbH (Berlin-Buch,Germany). For the assay 50 nl of a 100fold concentrated solution of thetest compound in DMSO was pipetted into a black low volume 384wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of Akt2 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl₂, 1mM dithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μl of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μl assay volume is 10 μM) and substrate (1.67 μM=>final conc. in the 5μl assay volume is 1 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofAkt2 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 0.2 ng/μl(final conc. in the 5 μl assay volume). The reaction was stopped by theaddition of 5 μl of a solution of HTRF detection reagents (200 nMstreptavidine-XL665 [Cisbio] and 1.5 nM anti-phosho-Serine antibody[Millipore, cat. #35-001] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouseIgG antibody [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA,0.1% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). Theresulting mixture was incubated 1 h at 22° C. to allow the binding ofthe biotinylated phosphorylated peptide to the streptavidine-XL665 andthe antibodies. Subsequently the amount of phosphorylated substrate wasevaluated by measurement of the resonance energy transfer from theanti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100-fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit using an in-house software.

Preferred compounds of the present invention show in either the Akt1 orAkt2 kinase assay: median IC₅₀<5 μM or greater than 50% inhibition at 5μM, more preferably, median IC₅₀<0.5 μM or greater than 50% inhibitionat 0.5 μM, even more preferably, median IC₅₀≦0.1 μM or greater than 50%inhibition at 0.1 μM.

The following Table gives selected data for selected Examples of thepresent invention.

Akt1 median Akt2 median Example IC₅₀ (nM) IC₅₀ (nM) 1 170.0 380.0 2 65.097.0 3 120.0 70.0 4 85.0 190.0 5 5.2 18.0 6 4.2 80.0 7 6.9 9.7 8 450.0400.0 9 3.9 18.0 10 2.6 4.1 11 130.0 110.0 12 21.0 38.0 13 78.0 42.0 149.8 65.0 15 4.4 56.0 16 160.0 160.0 17 43.0 92.0 18 86.0 53.0 19 15.042.0 20 120.0 170.0 21 73.0 130.0 22 8.0 18.0 23 1200.0 190.0 24 35.081.0 25 190.0 160.0 26 6.3 10.0 27 15.0 29.0 28 5.0 5.4 29 56.0 78.0 3051.0 58.0 31 48.0 140.0 32 3700.0 3300.0 33 690.0 Not tested 34 3.9 14.035 350.0 1200.0 36 17.0 54.0 37 580.0 510.0 38 370.0 140.0 39 38.0 160.040 1700.0 1400.0 41 33.0 66.0 42 20000.0 20000.0 43 36.0 110.0 44 190.0310.0 45 1200.0 6600.0 46 110.0 85.0 47 220.0 350.0 48 180.0 610.0 4968.0 120.0 50 44.0 27.0 51 42.0 81.0 52 26.0 15.0 53 9.2 2.4 54 12.035.0 55 45.0 56.0 56 6.6 16.0 57 25.0 29.0 58 110.0 280.0 59 65.0 110.060 7.2 24.0 61 4.1 3.7 62 16.0 62.0 63 46.0 120.0 64 4.8 12.0 65 3.1 2.666 51.0 180.0 67 58.0 96.0 68 21.0 66.0 69 310.0 750.0 70 130.0 110.0 7111.0 20.0 72 310.0 580.0 73 4.3 43.0 74 96.0 120.0 75 21.0 100.0 76 11.023.0 77 10.0 61.0 78 32.0 230.0 79 2000.0 2800.0 80 96.0 610.0Cellular Assays 3.0: p-AKT1/2/3-S473, -T308, and p-4E-BP1-T70 Assays

The molecular mechanism of action was investigated in a set ofexperiments to assess the inhibition of the PI3K-AKT-mTOR pathway inresponsive cell lines such as KPL-4 breast tumour cell line(PIK3CA^(H1047R), HER2^(O/E) and hormone independent). Thephospho-substrates of PI3K-AKT-mTOR axis were used as the read-outs toreflect pathway inhibition. Cells were seeded at 60-80% confluency perwell in 96-well cell culture plates. After overnight incubation at 37°C. 5% CO2, cells were treated with compounds and vehicle at 37° C. for 2hours. Thereafter, cells were lysed in 150 μl lysis buffer and thelevels of phospho-AKT at T308 and S473 and p-4E-BP1 at T70 sites weredetermined with the corresponding AlphaScreen® SureFire® assay kits(Perkin Elmer: 4E-BP1 Assay Kit Cat #TRG4E2S1K; Akt 1/2/3 p-Ser 473#TGRA4S500 and Akt 1/2/3 p-Thr 308 #TGRA3S500 as well as IgG detectionKit #6760617M) as described in the manuals. All measurements where atleast done in duplicates and confirmed by independent repetition.

Alternatively pAKT-S473 was measured using the “Akt Duplex” of theMULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat#N41100B-1)following manufacturers instructions. Each assay used 20 μg of proteinextract and measured total AKT and p-AKT content simultaneously in onewell. All measurements where at least done in duplicates and confirmedby independent repetition. Values for P-AKT are expressed as percentageof P-AKT level compared to total-AKT content of the extracts.

The following Table gives selected data for selected Examples of thepresent invention.

pAKT-S743 median P4EBP1-T70 median Example IC₅₀ (nM) IC₅₀ (nM) 1 160.0Not tested 2 310.0 2100.0 3 360.0 4500.0 4 610.0 2400.0 5 0.9 35.0 6210.0 1300.0 7 27.0 1300.0 8 >10000.0 >10000.0 9 36.0 690.0 10 2.4 28.011 14.0 160.0 12 52.0 260.0 13 82.0 660.0 14 220.0 320.0 15 590.0 1700.016 520.0 2500.0 17 12.0 430.0 18 180.0 710.0 19 390.0 5100.0 20 520.01500.0 21 420.0 1700.0 22 0.3 23.0 23 1400.0 2900.0 24 200.0 500.0 2590.0 550.0 26 0.9 90.0 27 36.0 480.0 28 1.0 6.2 29 210.0 1300.0 30 400.02500.0 31 1800.0 4300.0 32 160.0 2200.0 33 2900.0 Not tested 34 3.1150.0 35 190.0 1700.0 36 26.0 1600.0 37 81.0 2500.0 38 20.0 530.0 39280.0 7500.0 40 2000.0 6100.0 41 >10000.0 >10000.0 42 120.0 2600.0 4396.0 1600.0 44 800.0 380.0 45 >10000.0 >10000.0 46 430.0 300.0 47 140.096.0 48 42.0 29.0 49 8.0 41.0 50 450.0 2000.0 51 590.0 1200.0 52 2.1 9.953 200.0 1000.0 54 690.0 1600.0 55 680.0 1800.0 56 570.0 360.0 57 250.01800.0 58 1000.0 10000.0 59 11.0 100.0 60 1.0 8100.0 61 0.5 2.0 62 0.435.0 63 3.8 0.3 64 0.9 84.0 65 1.4 22.0 66 17.0 180.067 >10000.0 >10000.0 68 3.7 5300.0 69 250.0 4400.0 70 5.7 2400.0 71 92.010000.0 72 1000.0 590.0 73 230.0 1700.0 74 450.0 1200.0 75 230.0 1500.076 120.0 940.0 77 460.0 1400.0 78 92.0 580.0 79 210.0 910.0 80 190.09800.0

Biological Assay 4.0: Tumor Cell Proliferation Assays

Compounds were tested in a cell-based assay that measures the capacityof the compounds to inhibit tumour cell proliferation following a 72 hdrug exposure. Cell viability is determined using CellTiter-Glow® (CTG,Promega, cat#G7571/2/3). The CellTiter-Glo® Luminescent Cell ViabilityAssay is a homogeneous method to determine the number of viable cells inculture.

Detection is based on using the luciferase reaction to measure theamount of ATP from viable cells. The amount of ATP in cells correlateswith cell viability. Within minutes after a loss of membrane integrity,cells lose the ability to synthesize ATP, and endogenous ATPases destroyany remaining ATP; thus the levels of ATP fall precipitously.

Cells were plated at 3000-5000 cells/well (depending on the cell lines)in 90 μL growth medium on MTPs (Corning; #3603, black plate, clear flatbottom). For each cell line assayed, cells were plated onto a separateplate for determination of fluorescence at t=0 hour and t=72 hour timepoints. Following overnight incubation at 37° C., chemiluminescencevalues for the t=0 samples were determined after adding 10 μl medium and100 μl CTG solution according to manufacture protocol. Plates for thet=72 hour time points were treated with compounds diluted into growthmedium at ten times final concentration added in 10 μL to the cellculture plate. Cells were then incubated for 72 hours at 37° C.Chemiluminescence values for the t=72 hour samples were determined. Fordata analysis, briefly, data from 24 h plate where used to reflect 100%inhibition of growth (“Ci”) and DMSO control for uninhibited growth(“C0”) and analyzed using MTS software package for IC₅₀ and Hillcoefficient. Experiments were controlled using a reference compound asstandard.

Preferred compounds of the present invention show in this assay aninhibition of cell growth of cell lines such as the KPL-4 breast cancercell line MCF-7 breast tumour cell line (PIK3CA^(E542K;E545K), hormonedependent) and LNCaP prostate tumour cell line with a median IC₅₀ of <10μM, more preferably, median IC50≦1 μM.

The following Table gives selected data for selected Examples of thepresent invention.

KLP-4 median MCF-7 median Example IC₅₀ (nM) IC₅₀ (nM) 1 1800.0 600.0 21700.0 1700.0 3 1700.0 1800.0 4 2400.0 1800.0 5 170.0 63.0 6 1100.01200.0 7 250.0 410.0 8 >10000.0 >10000.0 9 770.0 340.0 10 49.0 39.0 11630.0 470.0 12 2000.0 1800.0 13 1500.0 1100.0 14 1900.0 1800.0 15 1800.01800.0 16 2000.0 1800.0 17 Not tested Not tested 18 1600.0 1100.0 192000.0 1800.0 20 2600.0 1800.0 21 2000.0 1800.0 22 190.0 240.0 23 2200.02100.0 24 1700.0 1800.0 25 2000.0 1900.0 26 1800.0 1800.0 27 1800.01800.0 28 1900.0 1800.0 29 2000.0 1700.0 30 6000.0 2600.0 31 8400.01400.0 32 Not tested Not tested 33 Not tested Not tested 34 1100.0 330.035 6100.0 3000.0 36 1800.0 1700.0 37 3200.0 2000.0 38 740.0 510.039 >10000.0 6100.0 40 >10000.0 8400.0 41 >10000.0 >10000.0 42 2800.04200.0 43 6200.0 6700.0 44 2000.0 1900.0 45 >10000.0 >10000.0 46 1900.01500.0 47 1700.0 1100.0 48 1100.0 1300.0 49 140.0 610.0 50 1700.0 1800.051 7000.0 1400.0 52 140.0 110.0 53 1700.0 870.0 54 740.0 1800.0 552000.0 1900.0 56 8200.0 1100.0 57 9400.0 2100.0 58 >10000.0 >10000.0 59Not tested Not tested 60 1500.0 73.0 61 33.0 56.0 62 Not tested Nottested 63 1600.0 760.0 64 360.0 150.0 65 470.0 280.0 66 2500.0 980.0 67Not tested Not tested 68 1500.0 680.0 69 10000.0 1500.0 70 2600.0 940.071 2000.0 780.0 72 2200.0 3000.0 73 1800.0 2000.0 74 2100.0 2000.0 751800.0 1800.0 76 1700.0 940.0 77 1900.0 1700.0 78 Not tested Not tested79 10000.0 10000.0 80 10000.0 10000.0

Example 5.0 Caco2 Permeability Assay

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cell per well on 24 well insert plates, 0.4 μm poresize, and grown for 15 days in DMEM medium supplemented with 10% fetalbovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/ml penicillin, 100 μg/mlstreptomycin (GIBCO) and 1% non essential amino acids (100×). Cells weremaintained at 37° C. in a humified 5% CO₂ atmosphere. Medium was changedevery 2-3 day. Before running the permeation assay, the culture mediumwas replaced by a FCS-free hepes-carbonate transport puffer (pH 7.2) Forassessment of monolayer integrity the transepithelial electricalresistance (TEER) was measured. Test compounds were predissolved in DMSOand added either to the apical or basolateral compartment in finalconcentration of 2 μM. Before and after 2 h incubation at 37° C. sampleswere taken from both compartments. Analysis of compound content was doneafter precipitation with methanol by LC/MS/MS analysis. Permeability(Papp) was calculated in the apical to basolateral (A→B) and basolateralto apical (B→A) directions. The apparent permeability was calculatedusing following equation:

P _(app)=(V _(r) /P _(o))(1/S)(P ₂ /t)

Where V_(r) is the volume of medium in the receiver chamber, P_(o) isthe measured peak area of the test drug in the donor chamber at t=0, Sthe surface area of the monolayer, P₂ is the measured peak area of thetest drug in the acceptor chamber after 2 h of incubation, and t is theincubation time. The efflux ratio basolateral (B) to apical (A) wascalculated by dividing the P_(app) B-A by the P_(app) A-B. In additionthe compound recovery was calculated. As assay control referencecompounds were analyzed in parallel.

Example 6.0 In Vivo Rat Pharmacokinetics

For in vivo pharmacokinetic experiments test compounds were administeredto male Wistar rats intravenously at doses of 0.5 to 1 mg/kg andintragastral at doses of 1 to 10 mg/kg formulated as solutions usingsolubilizers such as PEG400 in well-tolerated amounts.

For pharmacokinetics after intravenous administration test compoundswere given as i.v. bolus and blood samples were taken at 2 min, 8 min,15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing.Depending on the expected half-life additional samples were taken atlater time points (e.g. 48 h, 72 h). For pharmacokinetics afterintragastral administration test compounds were given intragastral tofasted rats and blood samples were taken at 5 min, 15 min, 30 min, 45min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on theexpected half-life additional samples were taken at later time points(e.g. 48 h, 72 h). Blood was collected into Lithium-Heparintubes(Monovetten®, Sarstedt) and centrifuged for 15 min at 3000 rpm. Analiquot of 100 μL from the supernatant (plasma) was taken andprecipitated by addition of 400 μL cold acetonitrile and frozen at −20°C. over night. Samples were subsequently thawed and centrifuged at 3000rpm, 4° C. for 20 minutes. Aliquots of the supernatants were taken foranalytical testing using an Agilent 1200 HPLC-system with LCMS/MSdetection. PK parameters were calculated by non-compartmental analysisusing a PK calculation software.

PK parameters derived from concentration-time profiles after i.v.:CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood:Total blood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) withCp/Cb being the ratio of concentrations in plasma and blood. PKparameters calculated from concentration time profiles after i.g.: Cmax:Maximal plasma concentration (in mg/L); Cmaxnorm: Cmax divided by theadministered dose (in kg/L); Tmax: Time point at which Cmax was observed(in h). Parameters calculated from both, i.v. and i.g.concentration-time profiles: AUCnorm: Area under the concentration-timecurve from t=0 h to infinity (extrapolated) divided by the administereddose (in kg*h/L); AUC(0-tlast)norm: Area under the concentration-timecurve from t=0 h to the last time point for which plasma concentrationscould be measured divided by the administered dose (in kg*h/L); t1/2:terminal half-life (in h); F: oral bioavailability: AUCnorm afterintragastral administration divided by AUCnorm after intravenousadministration (in %).

The person skilled in the art will be aware of methods to show in vivoefficacy of anti-cancer compounds. By way of illustration, the followingexample describes methods of quantifying the in vivo efficacy in a mousexenograft model. The skilled person will be able to apply suchprinciples to derive models from alternative tumor material.

Example 7.0 In Vivo Xenograft Mechanism of Action Study

To demonstrate that compounds act in tumours by the anticipated mode ofaction phosphorylation of the AKT protein was investigated in KPL-4breast tumours treated once with 50 mg/kg compound.

To this extent KPL-4 human breast tumours were xenografted onto athymicnude mice. KPL-4 tumour cells were cultivated according to ATCCprotocols in recommended media contained 10% FCS and harvested fortransplantation in a subconfluent (70%) state. 3×10⁶ tumour cellssuspended in 50% Matrigel were subcutaneously implantated into theinguinal region of female mice. Tumours were allowed to grow to thepredetermined size of 60-80 mm². When the tumours were approximately insize, the animals were randomized to treatment and control groups(groups size: 9 animals) and treatment was started. Animals were treatedonce with 50 mg/kg compound or vehicle per oral administration (p.o.)carried out via a gastric tube. Treatment of each animal was based onindividual body weight. At 2, 5 and 24 hours post treatment 3 animalseach were sacrificed and the KPL-4 tumours excised. Tumour samples ofapproximately 5×5×5 mm were lysed on ice in MSD lysis buffer in thepresence of protease and phosphatase inhibitors using Tissue Lyzer(Qiagen, Germany). The levels of p-AKT S473 in extracts from tumourtissue were analysed in an ELISA based assay. This assay is based on the“Akt Duplex” of the MULTI-SPOT® Assay System (Fa. Meso Scale Discovery,Cat#N41100B-1) following manufacturers instructions. Each assay used 20μg of protein extract and measured total AKT and p-AKT contentsimultaneously in one well. All measurements where at least done induplicates and confirmed by independent repetition.

Values for P-AKT are expressed as percentage of P-AKT level compared tototal-AKT content of the extracts. Vehicle treated tumours were analyzedto determine the basal level of P-AKT in this model and used as anormalization control to determine the % P-AKT relative to vehiclelevels.

Preferred compounds of the present invention show in this assay:relative to vehicle levels P-AKT<30% at 2 hours post treatment, morepreferably at 5 hours post treatment, even more preferably at 24 hourspost treatment.

Example 7.1 In Vivo Xenograft Efficacy Study

To determine the therapeutic efficacy and tolerability of compounds,tumour growth of KPL-4 breast tumours xenografted onto nude mice may beobserved. Mice were treated either with vehicle or compounds.

To this extent KPL-4 xenografts were established as described above.Tumours were allowed to grow to the predetermined size of 25-35 mm².When the tumours were approximately in size, the animals were randomizedto treatment and control groups (groups size: 8 animals) and treatmentwas started.

Treatment of each animal was based on individual body weight and oraladministration (p.o.) was carried out via a gastric tube. The oralapplication volumes were 10 ml/kg for mice. Mice were treated once dailywith 50 mg/kg compounds.

Tumour response was assessed by determination of the tumour area(product of the longest diameter and its perpendicular) using acalliper. The animal body weight was monitored as a measure fortreatment-related toxicity. Measurement of tumour area and body weightwere performed 2-3 times weekly. Statistical analysis was assessed usingthe SigmaStat software. A one way analysis of variance was performed,and differences to the control were compared by a pair-wise comparisonprocedure (Dunn's method). T/C ratios (Treatment/Control) werecalculated with final tumour weights at study end.

1. A compound of formula (I) in which

R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,—S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from 1-6C-alkyl,1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl,2-6C-alkynyl, wherein said group being optionally substituted, one ormore times, identically or differently, with a substituent selectedfrom: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7-cycloalkyl, 3-7C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6,halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl),NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-6C-alkyl,—S(O)₂NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy,3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl,2-6C-alkynyl, wherein said group being optionally substituted, one ormore times, identically or differently, with a substituent selectedfrom: hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-7C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano,CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11,—S(O)_(n)-1-6C-alkyl, —S(O)₂NR5R6 or a group selected from 1-6C-alkyl,1-6C-alkoxy 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl,-(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl,—O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl,—O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl,NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl, wherein said group beingoptionally substituted, one or more times, identically or differently,with a substituent selected from: hydroxy, halogen, 1-6C-alkyl,1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10,—NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11, 3-7C-heterocyclyl, aryl, R4 isphenyl which is optionally substituted one, two or three times,identically or differently, with a halogen atom; R5 is hydrogen,1-6C-alkyl, R6 is hydrogen, 1-6C-alkyl, R8 is hydrogen, 1-6C-alkyl whichoptionally is substituted with hydroxy, R9 is hydrogen, 1-6C-alkyl, R10is hydrogen, 1-6C-alkyl, R11 is hydrogen, 1-6C-alkyl, X, Y is CH₂; n is0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of saidcompound, or a salt of said N-oxide, tautomer or stereoisomer.
 2. Thecompound according to claim 1 wherein R1 is hydrogen, hydroxy, NR5R6,halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl),NHC(O)(1-6C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-3C-alkyl,—S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy,3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,-(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,—O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,—O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl,2-3C-alkynyl, wherein said group being optionally substituted, one ormore times, identically or differently, with a substituent selectedfrom: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-6-cycloalkyl, 3-6C-heterocyclyl, aryl, R2 is hydrogen, hydroxy, NR5R6,halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl),NHC(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11, —S(O)_(n)-1-3C-alkyl,—S(O)₂NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy,3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,-(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,—O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,—O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl,2-3C-alkynyl, wherein said group being optionally substituted, one ormore times, identically or differently, with a substituent selectedfrom: hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11,3-6C-heterocyclyl, aryl, R3 is hydrogen, hydroxy, NR5R6, halogen, cyano,CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O)₂R11, NHC(O)NHR11,—S(O)_(n)-1-3C-alkyl, —S(O)₂NR5R6 or a group selected from 1-3C-alkyl,1-3C-alkoxy 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl,-(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl,—O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl,—O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl,NHC(O)(1-3C-alkyl), 2-3C-alkenyl, 2-3C-alkynyl, wherein said group beingoptionally substituted, one or more times, identically or differently,with a substituent selected from: hydroxy, halogen, 1-3C-alkyl,1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10,—NHC(O)R11, —NHC(O)NHR11, —NHS(O)₂R11, 3-6C-heterocyclyl, aryl, R4 isphenyl which is optionally substituted one, two or three times,identically or differently, with a halogen atom; R5 is hydrogen,1-3C-alkyl, R6 is hydrogen, 1-3C-alkyl, R8 is hydrogen, 1-3C-alkyl whichoptionally is substituted with hydroxy, R9 is hydrogen, 1-3C-alkyl, R10is hydrogen, 1-3C-alkyl, R11 is hydrogen, 1-3C-alkyl, X, Y is CH₂; n is0, 1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of saidcompound, or a salt of said N-oxide, tautomer or stereoisomer.
 3. Thecompound according to claim 1 wherein R1 is hydrogen, hydrogen, hydroxy,NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), NR5R6 or a group selectedfrom 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl, 1-4C-alkoxy, whereinsaid group being optionally substituted, one or more times, identicallyor differently, with a substituent selected from: halogen, 1-6C-alkyl,1-6C-alkoxy, —C(O)OR10, 3-7-cycloalkyl, aryl, R2 is hydrogen,1-6C-alkyl, R3 is hydrogen, hydroxy, NR5R6, halogen, CO(NR8R9), C(O)OR8,C(O)(1-6C-alkyl), NHS(O)2R11, S(O)n-1-6C-alkyl, or a group selected from1-6C-alkyl, 1-6C-alkoxy aryl, NHC(O)(1-6C-alkyl), 2-6C-alkenyl, whereinsaid group being optionally substituted, one or more times, identicallyor differently, with a substituent selected from: halogen, —C(O)OR10, R4is phenyl, R5 is hydrogen, R6 is hydrogen, R8 is hydrogen, 1-4C-alkyl,which optionally is substituted with hydroxy, R9 is hydrogen,1-4C-alkyl, R10 is, 1-4C-alkyl, R11 is 1-4C-alkyl, X, Y is CH₂ n is 0,1, 2; or an N-oxide, a salt, a tautomer or a stereoisomer of saidcompound, or a salt of said N-oxide, tautomer or stereoisomer.
 4. Acompound according to claim 1 wherein R1 is hydrogen, hydroxyl, amino,methoxy, ethoxy, butoxy, pyridine-3-yl, pyridine-4-yl, pyrazol-3-yl,1-methyl-pyrazol-3-yl, imidazole-2-yl, methyl, propyl, —O—(CH₂)—O—CH₃,—O—CH₂-phenyl, —O—CH₂-cyclopropyl, —C(O)OCH₃, —C(O)—NHCH₃, —C(O)—NH₂,4-fluoro-phenyl, —(CH₂)₂—C(O)OCH₃, cyclopropyl, —NH—C(O)CH₃, R2 ishydrogen, methyl, R3 is hydrogen, hydroxy, amino, methyl, ethyl,methoxy, ethoxy, —O—CH₂—C(O)OCH₃, —S—CH₃, —SO₂—CH₃, bromine, chlorine,trifluoromethyl, C(O)NH₂, COOH, C(O)OCH₃, C(O)OCH₂CH₃, C(O)NH₂,C(O)NHCH₃, C(O)N(CH₃)₂, C(O)NH(CH₂)₂—OH, —CH═CH₂, 4-fluoro-phenyl,NHC(O)CH₃, NHC(O)CF₃, NH—SO₂—CH₃, C(O)CH₃, R4 is phenyl X, Y is CH2 oran N-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 5. A compound accordingto claim 1 selected from the group consisting of1-[4-(6-Methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-[4-(6-Ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-{4-[3-Phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine Ethyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6-carboxamide1-[4-(6-Methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6-carboxylic acid1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide1-[4-(8-Methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate1-[4-(6-Ethyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[6-Methoxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanami1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine HCl salt1-[4-(6,8-Diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(6-Chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine1-[4-(8-Methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[6-Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(3-Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]- cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[3-Phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide1-{4-[8-(Benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6-Chloro-8-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]- pyridazin-8-ol1-{4-[6-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazine-6,8-dicarboxamide2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-amine1-{4-[6-(Methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}acetamideN-{2-[4-(1-1-{4-[6-(Methylsulfonyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylateN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}-2,2,2-trifluoroacetamide1-[4-(6-Bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine 1-{4-[6,8-Bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}ethanone1-{4-[8-(4-Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-6-yl}methanesulfonamide1-[4-(6-Chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutanamine1-[4-(3-Phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutanamine 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-amineN-{2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]-pyridazin-8-yl}acetamide1-[4-(6-Chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate2-[4-(1-Aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide1-[4-(6-Methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutanamine1-{4-[7,8-Dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6-Ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine Methyl2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxylate Methyl2-[4-(1-aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate tert-Butyl{1-[4-(8-acetamido-3-phenylimidazo[1,2-b]-pyridazin-2-yl)phenyl]cyclobutyl}carbamate2-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-8-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-ethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid2-[4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide2-[4-(1-Aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6- carboxamide Methyl3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-imidazo[1,2-b]pyridazin-8-yl}propanoate1-{4-[6-Methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Methoxy-8-(1-methyl-1H-pyrazol-5-yl)-3-phenyl-imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine1-{4-[6-Methoxy-3-phenyl-8-(pyridin-4-yl)imidazo[1,2-b]-pyridazin-2-yl]phenyl}cyclobutanamine1-[4-(6,8-Diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine1-[4-(8-Butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine1-[4-(6-Ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutanamine2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]- pyridazin-6-olMethyl ({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo-[1,2-b]pyridazin-6-yl}oxy)acetate


6. Process for the manufacture of compounds of general formula (I)according to claim 1 by reacting a compound of general formula (II)

wherein R1-R4 have the meaning as stated in claim 1 and Rx,Ry are R6, ora protecting group, wherein transformation to a compound of generalformula (I) is accomplished by use of an appropriate deprotectionreaction
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. A pharmaceuticalcomposition comprising at least one compound of general formula (I)according to claim 1, together with at least one pharmaceuticallyacceptable additive.
 11. A pharmaceutical composition comprising a firstactive ingredient, which is at least one compound of general formula (I)according to claim 1, and a second active ingredient, which is at leastone further anti-cancer agent.
 12. (canceled)